Substituted bicyclic heteroaryl compounds

ABSTRACT

Disclosed are azaindazole compounds of Formula (I): 
                         
or a pharmaceutically acceptable salt thereof, wherein: X is O and Y is N; or X is S and Y is CH; Z is CR 2  or N; Q is a heteroaryl; and R 1  is defined herein. Also disclosed are methods of using such compounds in the treatment of at least one CYP17 associated condition, such as, for example, cancer, and pharmaceutical compositions comprising such compounds.

This application is a divisional application, which claims priority toU.S. patent application Ser. No. 14/598,721, filed Jan. 16, 2015, whichis a divisional application of U.S. patent application Ser. No.14/347,893, filed Mar. 27, 2014, which claims priority to national phaseapplication under 35 U.S.C. §371 of International Patent Application No.PCT/US2012/057406, filed Sep. 27, 2012, which claims priority toprovisional application U.S. 61/539,570, filed Sep. 27, 2011, thecontents of which are herein incorporated by reference.

The present invention generally relates to substituted bicyclicheteroaryl compounds useful as CYP17 inhibitors. Provided herein aresubstituted bicyclic heteroaryl compounds, compositions comprising suchcompounds, and methods of their use. The invention further pertains topharmaceutical compositions comprising at least one compound accordingto the invention that is useful for the treatment of conditions relatedto the CYP17 enzyme, such as cancer and other proliferative diseases.

Prostate cancer is the second leading cause of cancer related mortalityin American men. In 2007, there were 218,890 new cases with 27,000deaths associated with prostate cancer. It is well known that androgens,such as testosterone and dihydrotestosterone, drive the growth of theprostate as well as prostate cancer at the level of the androgenreceptor. The standard of care for advanced hormone sensitive prostatecancer involves surgical or chemical castration with a leutenizingreleasing hormone agonist/antagonist to remove the androgens produced inthe gonads from circulation. However, approximately 90% of androgens areproduced in the testes with the remaining 10% being produced through theaction of the adrenal gland. Thus, castration does not alleviate theaction of all androgens. Further once a patient progresses to castrationresistant prostate cancer, androgens are also produced at the level ofthe tumor, making treatment with antiandrogens more difficult.

The cytochrome P450 CYP17 is responsible for the biosynthesis of bothdihydroepiandrostenedione and androstenedione which are precursors ofboth androgens and estrogen. Thus the production of all androgens andestrogens produced in the human body is mediated by CYP17. Blocking thisenzyme would inhibit the production of gonadal, adrenal and tumoralandrogens and could offer a new treatment option for prostate cancer andestrogen receptor-positive breast cancer patients.

Clinical proof-of-concept for CYP17 as a target for prostate cancer hasbeen achieved with the antifungal ketoconazole and the steroidal CYP17inhibitor abiraterone, which has progressed to Phase III clinical trialsfor prostate cancer.

There remains a need for compounds that are useful as inhibitors ofCYP17 enzymes.

Applicants have found potent compounds that have activity as CYP17inhibitors. These compounds are provided to be useful as pharmaceuticalswith desired stability, bioavailability, therapeutic index, and toxicityvalues that are important to their drugability.

SUMMARY OF THE INVENTION

The present invention fills the foregoing need by providing substitutedbicyclic heteroaryl compounds, which are useful as inhibitors of CYP17enzymes, including salts and prodrugs thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier; and at least onecompound of Formula (I), or salts or prodrugs thereof.

The present invention also provides a method of treating a disease ordisorder associated with the activity of the CYP17 enzyme, the methodcomprising administering to a mammalian patient a compound of Formula(I) or pharmaceutically acceptable salts or prodrugs thereof.

The present invention also provides processes and intermediates formaking the compounds of Formula (I) or salts or prodrugs thereof.

The present invention also provides the compounds of Formula (I), orpharmaceutically acceptable salts or prodrugs thereof, for use intherapy.

The present invention also provides use of a compound of Formula (I) orpharmaceutically acceptable salts or prodrugs thereof, for themanufacture of a medicament for the treatment of cancer.

The compounds of Formula (I) and compositions comprising the compoundsare inhibitors of CYP17 enzymes, and may be used in treating,prevention, or curing various CYP17 enzyme related conditions.Pharmaceutical compositions comprising these compounds are useful intreating, preventing, or slowing the progression of diseases ordisorders in a variety of therapeutic areas, such as cancer.

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION

The first aspect of the invention provides compounds of Formula (I):

or pharmaceutically acceptable salts or prodrugs thereof, wherein:X is O and Y is N; or X is S and Y is CH;Z is CR² or N;Q is:

-   (i)

or

-   (ii) 9- to 10-membered bicyclic heteroaryl selected from

wherein Ring A is a 5- to 6-membered aryl or heteroaryl fused ring;R¹ is:

-   (i) H, halo, C₁₋₄fluoroalkyl, C₁₋₆alkoxy, C₁₋₄fluoroalkoxy,    —S(C₁₋₄fluoroalkyl), —O(C₁₋₄alkylenyl)O(C₁₋₃alkyl),    —O(CH₂)₁₋₄N(C₁₋₃alkyl)₂, —O(C₃₋₆alkynyl), or —O(methylpiperidinyl);-   (ii) phenyl substituted with zero to 2 substituents independently    selected from F, Cl, —CF₃, and/or —OCH₃;-   (iii) C₃₋₆cycloalkyl, morpholinyl, thiazolyl, pyridinyl,    pyridazinyl, or pyrazinyl; or-   (iv) —O(CH₂)₁₋₄R^(x) wherein R^(x) is imidazolyl, thiazolyl, phenyl,    fluorophenyl, chlorophenyl, methoxyphenyl, naphthalenyl, or    pyrazinyl;-   R² is H or —NHS(O)₂(C₁₋₄alkyl); and    R³ is:-   (i) F, Cl, C₁₋₄alkyl, C₁₋₄alkoxy, or C₁₋₄fluoroalkoxy;-   (ii) C₃₋₆cyclopropyl, morpholinyl, pyrazolyl, imidazolyl, or    triazolyl;-   (iii) —O(CH₂)₁₋₄R^(y) wherein R^(y) is phenyl, morpholinyl, or    pyridazinyl;-   (iv) pyrrolidinyl substituted with zero to 2 substituents    independently selected from —CH₃ and/or —OH; or-   (v) —NH₂, —NH(C₁₋₄alkyl), —NH(C₂₋₃fluoroalkyl), or    —NH(C₃₋₆cycloalkyl).

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein X is O and Y is N; and Z,R¹, and Q are defined in the first aspect. Compounds of this embodimenthave the structure of Formula (II):

Included in this embodiment are compounds in which Z is CR² and R¹ is:(i) Cl, —NH₂, —CH₂CH₂CF₃, C₁₋₆alkoxy,fluoroethoxy, —SCH₂CF₃, —OCH₂CH₂OCH₃, —OCH₂CH₂N(CH₃)₂, —O(CH₂C≡H), or—O(methylpiperidinyl); (ii) phenyl substituted with zero to 2substituents independently selected from F, Cl, and/or —OCH₃; (iii)cyclopropyl, thiazolyl, pyridinyl, pyridazinyl, or pyrazinyl; or (iv)—O(CH₂)₁₋₄R^(x) wherein R^(x) is imidazolyl, thiazolyl, phenyl,chlorophenyl, methoxyphenyl, naphthalenyl, or pyrazinyl.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein X is S and Y is CH; and Z,R¹, and Q are defined in the first aspect. Compounds of this embodimenthave the structure of Formula (III):

Included in this embodiment are compounds in which Z is CR² and R¹ is H,pyridinyl, or phenyl substituted with 1 to 2 substituents independentlyselected from F and/or Cl.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein Z is CR²; and X, Y, R¹,R², and Q are defined in the first aspect. Compounds of this embodimenthave the structure of Formula (IV):

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein Z is N; and X, Y, R¹, andQ are defined in the first aspect. Compounds of this embodiment have thestructure of Formula (V):

Included in this embodiment are compounds of Formula (V) in which Q is:

and R³ is defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein X is O, Y is N; Z is CR²;and R¹ and Q are defined in the first aspect. Compounds of thisembodiment have the structure of Formula (VI):

Included in this embodiment are compounds of Formula (VI) in which Q is:

and R³ is defined in the first aspect. Also included in this embodimentare compounds in which R³ is (i) Cl, —CH₃, C₁₋₃alkoxy, or fluoroethoxy;(ii) cyclopropyl, morpholinyl, pyrazolyl, imidazolyl, or triazolyl;(iii) —O(CH₂)₁₋₂R^(y) wherein R^(y) is phenyl, morpholinyl, orpyridazinyl; (iv) pyrrolidinyl substituted with —CH₃ and —OH; or(v) —NH₂, —NH(CH₂—CF₃), or —NH(cyclopropyl).

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein X is O, Y is N; Z is N;and R¹, R², and Q are defined in the first aspect. Compounds of thisembodiment have the structure of Formula (VII):

Included in this embodiment are compounds of Formula (VII) in which Qis:

and R³ is defined in the first aspect. Examples of suitable R³ groupsinclude —CH₃ and —NH₂.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein X is S, Y is CH; Z is CR²;and R¹, R², and Q are defined in the first aspect. Compounds of thisembodiment have the structure of Formula (VIII):

Included in this embodiment are compounds of Formula (VIII) in which Qis:

and R³ is defined in the first aspect. Examples of suitable R3 groupsinclude —CH₃ and cyclopropyl.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein X is S, Y is CH; Z is N;and R¹ and Q are defined in the first aspect. Compounds of thisembodiment have the structure of Formula (IX):

Included in this embodiment are compounds of Formula (IX) in which Q is:

and R³ is defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein Q is:

and X, Y, Z, R¹, and R³ are defined in the first aspect. Included inthis embodiment are compounds in which Q is:

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein Q is a 9- to 10-memberedbicyclic heteroaryl selected from:

wherein Ring A is a 5- to 6-membered aryl or heteroaryl fused ring; andX, Y, Z, R¹, and R³ are defined in the first aspect. Included in thisembodiment are compounds in which Q is:

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein Q is:

and X, Y, Z, R¹, and R³ are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein R¹ is H, halo,C₁₋₄fluoroalkyl, C₁₋₆alkoxy, C₁₋₄fluoroalkoxy, —S(C₁₋₄fluoroalkyl),—O(C₁₋₄alkylenyl)O(C₁₋₃alkyl), —O(CH₂)₁₋₄N(C₁₋₃alkyl)₂, —O(C₃₋₆alkynyl),or —O(methylpiperidinyl); and X, Y, Z, and Q are defined in the firstaspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein R¹ is phenyl substitutedwith zero to 2 substituents independently selected from F, Cl, —CF₃,and/or —OCH₃; and X, Y, Z, and Q are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein R¹ is C₃₋₆cycloalkyl,morpholinyl, thiazolyl, pyridinyl, pyridazinyl, or pyrazinyl; and X, Y,Z, and Q are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein R¹ is —O(CH₂)₁₋₄R^(x)wherein R^(x) is imidazolyl, thiazolyl, phenyl, fluorophenyl,chlorophenyl, methoxyphenyl, naphthalenyl, or pyrazinyl; and X, Y, Z,and Q are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein Z is CR²; R² is H; and X,Y, and Q are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein Z is CR²; R² is—NHS(O)₂(C₁₋₄alkyl); and X, Y, and Q are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein:

Q is

R³ is F, Cl, C₁₋₄alkyl, C₁₋₄alkoxy, or C₁₋₄fluoroalkoxy;and X, Y, and Z are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein:

Q is

R³ is C₃₋₆cyclopropyl, morpholinyl, pyrazolyl, imidazolyl, or triazolyl;and X, Y, and Z are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein:

Q is

R³ is —O(CH₂)₁₋₄R^(y) wherein R^(y) is phenyl, morpholinyl, orpyridazinyl;and X, Y, and Z are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein:

Q is

-   R³ is pyrrolidinyl substituted with zero to 2 substituents    independently selected from —CH₃ and/or —OH;    and X, Y, and Z are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein:

Q is

R³ is —NH₂, —NH(C₁₋₄alkyl), —NH(C₂₋₃fluoroalkyl), or—NH(C₃₋₆cycloalkyl);and X, Y, and Z are defined in the first aspect.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein:

R¹ is:

-   (i) H, Cl, —CH₂CH₂CF₃, C₁₋₆alkoxy, fluoroethoxy, —SCH₂CF₃,    —OCH₂CH₂OCH₃, —OCH₂CH₂N(CH₃)₂, —O(CH₂C≡H), or —O(methylpiperidinyl);-   (ii) phenyl substituted with zero to 2 substituents independently    selected from F, Cl, —CF₃, and/or —OCH₃;-   (iii) cyclopropyl, morpholinyl, thiazolyl, pyridinyl, pyridazinyl,    or pyrazinyl; or-   (iv) —O(CH₂)₁₋₄R^(x) wherein R^(x) is imidazolyl, thiazolyl, phenyl,    chlorophenyl, methoxyphenyl, naphthalenyl, or pyrazinyl;    R² is H or —NHS(O)₂CH₃; and    R³ is:-   (i) Cl, —CH₃, C₁₋₃alkoxy, or fluoroethoxy;-   (ii) cyclopropyl, morpholinyl, pyrazolyl, imidazolyl, or triazolyl;-   (iii) —O(CH₂)₁₋₂R^(y) wherein R^(y) is phenyl, morpholinyl, or    pyridazinyl;-   (iv) pyrrolidinyl substituted with —CH₃ and —OH; or-   (v) —NH₂, —NH(CH₂CF₃), or —NH(cyclopropyl).

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein:

X is O;

Y is N:

Z is CR²;

R¹ is:

-   (i) Cl, —NH₂, —CH₂CH₂CF₃, C₁₋₆alkoxy, fluoroethoxy, —SCH₂CF₃,    —OCH₂CH₂OCH₃, —OCH₂CH₂N(CH₃)₂, —O(CH₂C≡H), or —O(methylpiperidinyl);-   (ii) phenyl substituted with zero to 2 substituents independently    selected from F, Cl, and/or —OCH₃;-   (iii) cyclopropyl, thiazolyl, pyridinyl, pyridazinyl, or pyrazinyl;    or-   (iv) —O(CH₂)₁₋₄R^(x) wherein R^(x) is imidazolyl, thiazolyl, phenyl,    chlorophenyl, methoxyphenyl, naphthalenyl, or pyrazinyl;    R² is H or —NHS(O)₂CH₃; and    R³ is:-   (i) Cl, —CH₃, C₁₋₃alkoxy, or fluoroethoxy;-   (ii) cyclopropyl, morpholinyl, pyrazolyl, imidazolyl, or triazolyl;-   (iii) —O(CH₂)₁₋₂R^(y) wherein R^(y) is phenyl, morpholinyl, or    pyridazinyl;-   (iv) pyrrolidinyl substituted with —CH₃ and —OH; or-   (v) —NH₂, —NH(CH₂CF₃), or —NH(cyclopropyl).

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein:

-   X is O:-   Y is N:-   Z is N;-   Q is

-   R¹ is Cl, morpholinyl, or phenyl substituted with zero to 2    substituents independently selected from F, Cl, and/or —OCH₃; and-   R³ is —CH₃ or —NH₂.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein:

-   X is S;-   Y is CH;-   Z is CR²;-   Q is

-   R¹ is H, pyridinyl, or phenyl substituted with 1 to 2 substituents    independently selected from F and/or Cl;-   R² is H or —NHS(O)₂CH₃; and-   R³ is —CH₃ or cyclopropyl.

One embodiment provides compounds of Formula (I) or pharmaceuticallyacceptable salts or prodrugs thereof, wherein:

-   X is S;-   Y is CH;-   Z is N;-   Q is

-   R¹ is thiazolyl, pyridinyl, pyrazinyl, or phenyl substituted with    zero to 2 substituents independently selected from F, Cl, and/or    —CF₃; and-   R³ is —CH₃, cyclopropyl, or —NH₂.

One embodiment provides a compound of Formula (I) wherein said compoundis selected from 7-(4-methylpyridin-3-yl)-3-phenylbenzo[d]isoxazole (1);7-(4-methoxypyridin-3-yl)-3-phenylbenzo[d]isoxazole (2);7-(4-chloropyridin-3-yl)-3-phenylbenzo[d]isoxazole (3);7-(4-methylpyrimidin-5-yl)-3-phenylbenzo[d]isoxazole (4);7-(isoquinolin-4-yl)-3-phenylbenzo[d]isoxazole (5);3-(4-fluorophenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (6);7-(4-chloropyridin-3-yl)-3-(4-fluorophenyl)benzo[d]isoxazole (7);3-(4-fluorophenyl)-7-(4-methoxypyridin-3-yl)benzo[d]isoxazole (8);3-(4-fluorophenyl)-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole (9);3-(4-fluorophenyl)-7-(isoquinolin-4-yl)benzo[d]isoxazole (10);7-(4-cyclopropylpyrimidin-5-yl)-3-(4-fluorophenyl)benzo[d]isoxazole(11);3-(4-fluorophenyl)-7-(4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)benzo[d]isoxazole(12); 3-(4-fluorophenyl)-7-(1,7-naphthyridin-5-yl)benzo[d]isoxazole(13);3-(4-fluorophenyl)-7-(pyrrolo[1,2-c]pyrimidin-4-yl)benzo[d]isoxazole(14);5-(3-(4-fluorophenyl)benzo[d]isoxazol-7-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine(15); 3-(4-fluorophenyl)-7-(4-morpholinopyrimidin-5-yl)benzo[d]isoxazole(16); 7-(4-methylpyridin-3-yl)-3-(pyridin-2-yl)benzo[d]isoxazole (17);7-(4-chloropyridin-3-yl)-3-(pyridin-2-yl)benzo[d]isoxazole (18);7-(isoquinolin-4-yl)-3-(pyridin-2-yl)benzo[d]isoxazole (19);7-(4-methylpyridin-3-yl)-3-(thiazol-2-yl)benzo[d]isoxazole (20);7-(4-chloropyridin-3-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole (21);7-(4-methylpyridin-3-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole (22);7-(isoquinolin-4-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole (23);7-(4-methoxypyridin-3-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole (24);7-(4-cyclopropylpyrimidin-5-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole (25);3-(pyrazin-2-yl)-7-(4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)benzo[d]isoxazole(26); 7-(4-methylpyrimidin-5-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole (27);3-cyclopropyl-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (28);3-cyclopropyl-7-(4-methoxypyridin-3-yl)benzo[d]isoxazole (29);7-(4-chloropyridin-3-yl)-3-cyclopropylbenzo[d]isoxazole (30);3-cyclopropyl-7-(4-cyclopropylpyrimidin-5-yl)benzo[d]isoxazole (31);3-cyclopropyl-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole (32);7-(4-methylpyridin-3-yl)-3-(pyridazin-3-yl)benzo[d]isoxazole (33);7-(4-chloropyridin-3-yl)-3-(pyridazin-3-yl)benzo[d]isoxazole (34);3-(5-fluoro-2-methoxyphenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole(35);3-(5-fluoro-2-methoxyphenyl)-7-(4-morpholinopyrimidin-5-yl)benzo[d]isoxazole(36);3-(5-fluoro-2-methoxyphenyl)-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole(37);7-(4-chloropyridin-3-yl)-3-(5-fluoro-2-methoxyphenyl)benzo[d]isoxazole(38);7-(4-cyclopropylpyrimidin-5-yl)-3-(5-fluoro-2-methoxyphenyl)benzo[d]isoxazole(39);3-(5-fluoro-2-methoxyphenyl)-7-(4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)benzo[d]isoxazole(40); 3-(5-fluoro-2-methoxyphenyl)-7-(isoquinolin-4-yl)benzo[d]isoxazole(41);5-(3-(5-fluoro-2-methoxyphenyl)benzo[d]isoxazol-7-yl)pyrimidin-4-amine(42);3-(4-fluoro-2-methoxyphenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole(43);7-(4-chloropyridin-3-yl)-3-(4-fluoro-2-methoxyphenyl)benzo[d]isoxazole(44);3-(4-fluoro-2-methoxyphenyl)-7-(4-morpholinopyrimidin-5-yl)benzo[d]isoxazole(45);3-(4-fluoro-2-methoxyphenyl)-7-(4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)benzo[d]isoxazole(46);3-(4-fluoro-2-methoxyphenyl)-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole(47);7-(4-cyclopropylpyrimidin-5-yl)-3-(4-fluoro-2-methoxyphenyl)benzo[d]isoxazole(48); 3-(4-fluoro-2-methoxyphenyl)-7-(isoquinolin-4-yl)benzo[d]isoxazole(49); 3-chloro-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (50);7-(4-(1H-pyrazol-1-yl)pyrimidin-5-yl)-3-(2-chlorophenyl)benzo[d]isoxazole(51);7-(4-(1H-1,2,4-triazol-1-yl)pyrimidin-5-yl)-3-(2-chlorophenyl)benzo[d]isoxazole(52);(R)-1-(5-(3-(2-chlorophenyl)benzo[d]isoxazol-7-yl)pyrimidin-4-yl)-3-methylpyrrolidin-3-ol(53);5-(3-(2-chlorophenyl)benzo[d]isoxazol-7-yl)-N-cyclopropylpyrimidin-4-amine(54); 3-(2-chlorophenyl)-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole(55); 3-(2-chlorophenyl)-7-(4-ethoxypyrimidin-5-yl)benzo[d]isoxazole(56);7-(4-(2H-1,2,3-triazol-2-yl)pyrimidin-5-yl)-3-(2-chlorophenyl)benzo[d]isoxazole(57); 3-(2-chlorophenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (58);3-(2-chlorophenyl)-7-(isoquinolin-4-yl)benzo[d]isoxazole (59);7-(4-(1H-imidazol-1-yl)pyrimidin-5-yl)-3-(2-chlorophenyl)benzo[d]isoxazole(60); 7-(isoquinolin-4-yl)-3-(2,2,2-trifluoroethoxy)benzo[d]isoxazole(61);7-(4-methylpyridin-3-yl)-3-(2,2,2-trifluoroethoxy)benzo[d]isoxazole(62); 3-isopropoxy-7-(isoquinolin-4-yl)benzo[d]isoxazole (63);3-isobutoxy-7-(isoquinolin-4-yl)benzo[d]isoxazole (64);7-(isoquinolin-4-yl)-3-(2,2,2-trifluoroethylthio)benzo[d]isoxazole (65);7-(isoquinolin-4-yl)-3-(2,2,2-trifluoroethylthio)benzo[d]isoxazole (66);3-(2-methoxyethoxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (67);3-(2-methoxyethoxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (68);3-isopropoxy-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (69);7-(4-methylpyridin-3-yl)-3-(2,2,2-trifluoroethylthio)benzo[d]isoxazole(70); 3-isobutoxy-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (71);3-(2-methoxyphenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (72);7-(4-(benzyloxy)pyrimidin-5-yl)-3-(2-methoxyphenyl)benzo[d]isoxazole(73);7-(4-(2-fluoroethoxy)pyrimidin-5-yl)-3-(2-methoxyphenyl)benzo[d]isoxazole(74);7-(4-isopropoxypyrimidin-5-yl)-3-(2,2,2-trifluoroethoxy)benzo[d]isoxazole(75);3-(2-methoxyphenyl)-7-(4-(2-morpholinoethoxy)pyrimidin-5-yl)benzo[d]isoxazole(76);3-(2-methoxyphenyl)-7-(4-(pyridazin-3-ylmethoxy)pyrimidin-5-yl)benzo[d]isoxazole(77);3-(2-methoxyphenyl)-7-(4-(pyridazin-3-ylmethoxy)pyrimidin-5-yl)benzo[d]isoxazole(78); 7-(4-chloropyridin-3-yl)-3-(2-methoxyphenyl)benzo[d]isoxazole(79); 7-(isoquinolin-4-yl)-3-(2-methoxyphenyl)benzo[d]isoxazole (80);7-(4-(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(2-methoxyphenyl)benzo[d]isoxazole(81); 3-(2-methoxyphenyl)-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole(82);3-(2-methoxyphenyl)-7-(4-morpholinopyrimidin-5-yl)benzo[d]isoxazole(83);3-(2-methoxyphenyl)-7-(pyrrolo[1,2-c]pyrimidin-4-yl)benzo[d]isoxazole(84);7-(4-methylpyridin-3-yl)-3-(3,3,3-trifluoropropyl)benzo[d]isoxazole(85);N-(3-amino-7-(4-methylpyridin-3-yl)benzo[d]isoxazol-4-yl)methanesulfonamide(104); 7-(4-methylpyridin-3-yl)-3-phenethoxybenzo[d]isoxazole (115);3-(4-chlorophenethoxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (116);7-(4-methylpyridin-3-yl)-3-(prop-2-ynyloxy)benzo[d]isoxazole (117);3-(3,3-dimethylbutoxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (118);3-(isopentyloxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (119);7-(4-methylpyridin-3-yl)-3-propoxybenzo[d]isoxazole (120);7-(4-methylpyridin-3-yl)-3-(3-phenylpropoxy)benzo[d]isoxazole (121);7-(4-methylpyridin-3-yl)-3-(4-phenylbutoxy)benzo[d]isoxazole (122);3-ethoxy-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (123);7-(4-methylpyridin-3-yl)-3-(naphthalen-2-ylmethoxy)benzo[d]isoxazole(124); 3-tert-butoxy-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (125);3-methoxy-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (126);3-(benzyloxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (127);3-(4-chlorobenzyloxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (128);3-(4-methoxybenzyloxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (129);3-(1-methylpiperidin-4-yloxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole(130); 3-isopropoxy-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (131);3-(2-(1H-imidazol-1-yl)ethoxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole(132); 7-(4-methylpyridin-3-yl)-3-(pyrazin-2-ylmethoxy)benzo[d]isoxazole(133); 7-(4-methylpyridin-3-yl)-3-(thiazol-2-ylmethoxy)benzo[d]isoxazole(134); and pharmaceutically acceptable salts and prodrugs thereof.

One embodiment provides a compound of Formula (I) wherein said compoundis selected from3-(4-fluorophenyl)-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine(86); 3-chloro-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine (87);7-(4-methylpyridin-3-yl)-3-morpholinoisoxazolo[4,5-b]pyridine (88);7-(4-methylpyridin-3-yl)-3-phenylisoxazolo[4,5-b]pyridine (89);3-(5-fluoro-2-methoxyphenyl)-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine(90);5-(3-(2-chloro-4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-amine(91);5-(3-(4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-amine(92); and pharmaceutically acceptable salts and prodrugs thereof.

One embodiment provides a compound of Formula (I) wherein said compoundis selected from7-(4-methylpyridin-3-yl)-3-(pyridin-2-yl)thieno[3,2-b]pyridine (93);7-(4-methylpyridin-3-yl)-3-(thiazol-2-yl)thieno[3,2-b]pyridine (94);7-(4-methylpyridin-3-yl)-3-(pyrazin-2-yl)thieno[3,2-b]pyridine (95);3-(4-fluorophenyl)-7-(4-methylpyridin-3-yl)thieno[3,2-b]pyridine (96);7-(4-methylpyridin-3-yl)-3-phenylthieno[3,2-b]pyridine (97);3-(4-fluorophenyl)-7-(4-methylpyrimidin-5-yl)thieno[3,2-b]pyridine (98);7-(4-cyclopropylpyrimidin-5-yl)-3-(4-fluorophenyl)thieno[3,2-b]pyridine(99); 5-(3-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)pyrimidin-4-amine(100);5-(3-(4-fluoro-2-(trifluoromethyl)phenyl)thieno[3,2-b]pyridin-7-yl)pyrimidin-4-amine(101);5-(3-(2,4-difluorophenyl)thieno[3,2-b]pyridin-7-yl)pyrimidin-4-amine(102);5-(3-(2-chloro-4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)pyrimidin-4-amine(103); and pharmaceutically acceptable salts and prodrugs thereof.

One embodiment provides a compound of Formula (I) wherein said compoundis selected fromN-(7-(4-methylpyridin-3-yl)benzo[b]thiophen-4-yl)methanesulfonamide(105);N-(7-(4-cyclopropylpyrimidin-5-yl)benzo[b]thiophen-4-yl)methanesulfonamide(106);N-(7-(4-cyclopropylpyridin-3-yl)benzo[b]thiophen-4-yl)methanesulfonamide(107); 5-(3-(4-fluorophenyl)benzo[b]thiophen-7-yl)-4-methylpyrimidine(108); 4-(3-(4-fluorophenyl)benzo[b]thiophen-7-yl)isoquinoline (109);4-(3-(2-chloro-4-fluorophenyl)benzo[b]thiophen-7-yl)isoquinoline (110);3-(3-(4-fluorophenyl)benzo[b]thiophen-7-yl)-4-methylpyridine (111);4-methyl-3-(3-(pyridin-2-yl)benzo[b]thiophen-7-yl)pyridine (112);3-(3-(2,4-difluorophenyl)benzo[b]thiophen-7-yl)-4-methylpyridine (113);3-(3-(2-chloro-4-fluorophenyl)benzo[b]thiophen-7-yl)-4-methylpyridine(114); and pharmaceutically acceptable salts and prodrugs thereof.

DEFINITIONS

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. Embodiments identified herein as exemplary or preferred areintended to be illustrative and not limiting.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Listed below are definitions of various terms used to describe thepresent invention. These definitions apply to the terms as they are usedthroughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, andI.

The term “alkyl” as used herein, refers to both branched andstraight-chain saturated aliphatic hydrocarbon groups containing, forexample, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1to 4 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl(e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscriptafter the symbol “C”, the subscript defines with more specificity thenumber of carbon atoms that a particular group may contain. For example,“C₁₋₆ alkyl” denotes straight and branched chain alkyl groups with oneto six carbon atoms.

As used herein, “alkylenyl” refers to a bivalent alkyl radical havingthe general formula —(CH₂)_(n)—, where n is 1 to 10. Non-limitingexamples include methylene, dimethylene, trimethylene, tetramethylene,pentamethylene, and hexamethylene. For example, “C₁₋₆alkylene” denotesstraight and branched chain alkylene groups with one to six carbonatoms. Further, for example, “C₀₋₄alkylene” denotes a bond and straightand branched chain alkylene groups with one to four carbon atoms.

The term “alkynyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least one carbon tocarbon triple bond. Exemplary such groups include ethynyl. For example,“C₂₋₆ alkynyl” denotes straight and branched chain alkynyl groups withtwo to six carbon atoms.

The term “fluoroalkyl” as used herein is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupssubstituted with one or more fluorine atoms. For example, “C₁₋₄fluoroalkyl” is intended to include C₁, C₂, C₃, and C₄ alkyl groupssubstituted with one or more fluorine atoms. Representative examples offluoroalkyl groups include, but are not limited to, —CF₃ and —CH₂CF₃.

The term “cyano” refers to the group —CN.

The term “cycloalkyl,” as used herein, refers to a group derived from anon-aromatic monocyclic or polycyclic hydrocarbon molecule by removal ofone hydrogen atom from a saturated ring carbon atom. Representativeexamples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in asubscript after the symbol “C”, the subscript defines with morespecificity the number of carbon atoms that a particular cycloalkylgroup may contain. For example, “C₃₋₆ cycloalkyl” denotes cycloalkylgroups with three to six carbon atoms.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom, for example, methoxygroup (—OCH₃).

“Fluoroalkoxy” and “—O(fluoroalkyl)” represent a fluoroalkyl group asdefined above attached through an oxygen linkage (—O—). For example,“C₁₋₄fluoroalkoxy” is intended to include C₁, C₂, C₃, and C₄fluoroalkoxy groups.

The term “aryl,” as used herein, refers to a group of atoms derived froma molecule containing aromatic ring(s) by removing one hydrogen that isbonded to the aromatic ring(s). Representative examples of aryl groupsinclude, but are not limited to, phenyl, naphthyl, indanyl, indenyl, and1,2,3,4-tetrahydronaphth-5-yl.

The term “benzyl,” as used herein, refers to a methyl group in which oneof the hydrogen atoms is replaced by a phenyl group.

The term “heteroatom” refers to oxygen (O), sulfur (S), and nitrogen(N).

The term “heteroaryl” refers to substituted and unsubstituted aromatic5- or 6-membered monocyclic groups and 9- or 10-membered bicyclic groupswhich have at least one heteroatom (O, S or N) in at least one of therings, said heteroatom-containing ring preferably having 1, 2, or 3heteroatoms independently selected from O, S, and/or N. Each ring of theheteroaryl group containing a heteroatom can contain one or two oxygenor sulfur atoms and/or from one to four nitrogen atoms provided that thetotal number of heteroatoms in each ring is four or less and each ringhas at least one carbon atom. The fused rings completing the bicyclicgroup may contain only carbon atoms and may be saturated, partiallysaturated, or unsaturated. The nitrogen and sulfur atoms may optionallybe oxidized and the nitrogen atoms may optionally be quaternized.Heteroaryl groups which are bicyclic or tricyclic must include at leastone fully aromatic ring but the other fused ring or rings may bearomatic or non-aromatic. The heteroaryl group may be attached at anyavailable nitrogen or carbon atom of any ring. The heteroaryl ringsystem may be unsubstituted or may contain one or more substituents.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazolyl.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydroisoindolyl, and tetrahydroquinolinyl.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; and alkali or organic saltsof acidic residues such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. The pharmaceuticallyacceptable salts of the present invention can be synthesized from theparent compound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., p. 1418 (Mack Publishing Company, Easton, Pa., 1985), thedisclosure of which is hereby incorporated by reference.

Salt(s) of the Formula (I) compounds can be formed by, for example,reacting a Formula (I) compound with, for example, an equivalent amountof acid or base in a medium that allows the newly formed salt to, forexample, either be precipitated out, or be isolated via lyophilization.Exemplary acidic salt(s) that the compounds of Formula (I) can form withinorganic and/or organic acids include, but are not limited to, forexample, include acetate, ascorbate, benzoate, benzenesulfonate,bisulfate, bitartrate, acid citrate, citrate, ethanesulfonate, formate,fumarate, gentisinate, gluconate, glucaronate, glutamate, hydrochloride,hydrobromide, hydroiodide, isonicotinate, maleate, mesylate,methanesulfonate, nitrate, pantothenate, phosphate, acid phosphate,saccharate, salicylate, succinate, sulfate, tartrate,p-toluenesulfonate, trifluoroacetate, lactate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Such salts can beformed in accordance with methods known to a person of ordinary skill inthe art.

Exemplary basic salt(s) that the compounds of Formula (I) can form withinorganic and/or organic bases include, but are not limited to, forexample, ammonium salts; alkali metal salts, such as, for example,sodium, lithium and potassium salts: alkaline earth metal salts, suchas, for example, calcium and magnesium salts; salts formed with organicbases, such as, for example, benzathines, dicyclohexylamines,2-amino-2-(hydroxymethyl)propane-1,3-diol (trisamine or tris),hydrabamines (such as, for example,N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glycamides, and t-butyl amines; salts formed with aminoacids, such as, for example, arginine and lysine; and salts formed byusing agents, such as, for example, lower alkyl halides (e.g., methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), and aralkyl halides (e.g., benzyl and phenethylbromides) to quaternize basic nitrogen-containing groups. Such salts canbe formed in accordance with methods known to a person of ordinary skillin the art.

In addition, compounds of Formula (I) are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% of acompound of Formula (I) (“substantially pure”), which is then used orformulated as described herein. Such “substantially pure” compounds ofFormula (I) are also contemplated herein as part of the presentinvention.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of Formula (I)) is a prodrug within the scopeand spirit of the invention.

The term “prodrugs” as employed herein includes amides and carbamatesformed by reacting one or more amino groups of compounds of Formula (I)with alkyl, alkoxy, or aryl substituted acylating agents employingprocedures known to those skilled in the art to generate amides, ureas,carbamates, and the like.

Various forms of prodrugs are well known in the art and are describedin:

a) Wermuth, C. G. et al., The Practice of Medicinal Chemistry, Ch. 31,(Academic Press, 1996);

b) Bundgaard, H., ed., Design of Prodrugs, (Elsevier, 1985);

c) Krogsgaard-Larson, P. et al., eds., A Textbook of Drug Design andDevelopment, Ch. 5, pp. 113-191 (Harwood Academic Publishers, 1991); and

d) Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism,(Wiley-VCH, 2003).

In addition, compounds of the Formula (I) are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% Formula (I)compound (“substantially pure” compound I), which is then used orformulated as described herein. Such “substantially pure” compounds ofthe Formula (I) are also contemplated herein as part of the presentinvention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to act as anantagonist of CYP17 enzyme, or effective to treat cancer.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

Compounds of the present invention may contain one or more additionalasymmetric carbon atoms and therefore exist in two or morestereoisomeric forms. The present invention includes all of the possibleindividual stereoisomers, the individual tautomeric forms thereof,together with mixtures thereof. Separation of diastereoisomers may beachieved by conventional techniques, e.g., by fractionalcrystallization, chromatography or HPLC of a stereoisomeric mixture of acompound of the present invention, or a suitable salt or derivativethereof. An individual enantiomer of the compound may also be preparedfrom a corresponding optically pure intermediate or by resolution, suchas by HPLC of the corresponding racemate using a suitable chiral supportor by fractional crystallization of the diastereoisomeric salts formedby reaction of the corresponding racemate with a suitable opticallyactive acid or base, as appropriate. All stereoisomers of the compoundsof the instant invention are contemplated, either in admixture or inpure or substantially pure form.

The compounds of the present invention are intended to include allisotopes of atoms occurring in the present compounds. Isotopes includethose atoms having the same atomic number but different mass numbers. Byway of general example and without limitation, isotopes of hydrogeninclude deuterium and tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising the compound of Formula (I) or apharmaceutically acceptable salt thereof in association with one or morenon-toxic, pharmaceutically-acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) and,if desired, other active ingredients. The compounds of Formula (I) maybe administered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, or parentally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly intrasternally andinfusion techniques, in dosage unit formulations containing conventionalpharmaceutically acceptable carriers, adjuvants, and vehicles. Forexample, the pharmaceutical carrier may contain a mixture of mannitol orlactose and microcrystalline cellulose. The mixture may containadditional components such as a lubricating agent, e.g., magnesiumstearate and a disintegrating agent such as crospovidone. The carriermixture may be filled into a gelatin capsule or compressed as a tablet.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 0.5 to 2000 mg,preferably from about 0.5 to 500 mg, more preferably from about 0.5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The amounts of compounds that are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex, the medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.01 to 100 mg/kg body weight, preferably between about0.05 and about 50 mg/kg body weight and most preferably between about0.05 to 20 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered orally, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl alcohol,and/or polyvinylpyrrolidone, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose.

The oily phase of the emulsions comprising compounds of Formula (I) maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (i.e., CAPTISOL®), cosolvent solubilization (i.e.,propylene glycol) or micellar solubilization (i.e., Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in propylene glycol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, and buffers. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Pharmaceutical compositions of this invention comprise the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, andoptionally an additional agent selected from any pharmaceuticallyacceptable carrier, adjuvant, and vehicle. Alternate compositions ofthis invention comprise a compound of the Formula (I) described herein,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that maybe used in the pharmaceutical compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants usedin pharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin,or chemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

UTILITY

The compounds of Formula (I) are useful for the treatment of cancer, forexample, cancers dependent upon androgen receptor signaling. Thesecompounds inhibit the activity of the CYP17 enzyme, which is involved inbiosynthesis of androgens and estrogens. Blocking this enzyme wouldinhibit the production of gonadal, adrenal, and tumoral androgens andoffers a new treatment option for cancers dependent upon androgenreceptor and estrogen receptor signaling, such as prostate cancer andestrogen receptor-positive breast cancer patients. Thus, the treatmentcomprises administering to the patient a compound of Formula (I) or apharmaceutically acceptable salt or prodrug thereof.

In one embodiment, a method is provided for treating cancer comprisingadministering compound of Formula (I) or a pharmaceutically acceptablesalt or prodrug thereof to a mammal in need thereof. The method of thisembodiment can be used to treat a variety of cancers, including, but notlimited to, breast cancer, ovarian cancer, and prostate cancer.Preferably, the method of this embodiment is used to treat prostatecancer or breast cancer. In one method of this embodiment, compound ofFormula (I) is administered in a therapeutically effective amount.

In one embodiment, provided are methods for treating cancer in a patientwherein the cancer is dependent upon CYP17 activation, comprisingadministering to the patient in need thereof a compound of Formula (I)or a pharmaceutically acceptable salt or prodrug thereof. In one methodof this embodiment, a compound of Formula (I) is administered to treatprostate cancer. In another method of this embodiment, a compound ofFormula (I) is administered to treat breast cancer. Preferably, atherapeutically effective amount of Compound (I) is administered.

The amount of a compound of Formula (I) which is administered and thedosage regimen for treating a particular cancer depends on a variety offactors, including the age, weight, sex and medical condition of thesubject, the type of disease, the severity of the disease, the route andfrequency of administration, and the particular compound employed. Thus,the dosage regimen may vary widely, but can be determined routinelyusing standard methods. A daily dose of about 0.01 to 500 mg/kg bodyweight, preferably between about 0.05 and about 50 mg/kg body weight andmost preferably between about 0.05 to 20 mg/kg body weight, may beappropriate may be appropriate. The daily dose can be administered inone to four doses per day.

In treating cancer, a combination of chemotherapeutic agents and/orother treatments (e.g., radiation therapy) is often advantageous. Thesecond (or third) agent may have the same or different mechanism ofaction than the primary therapeutic agent. It may be especially usefulto employ cytotoxic drug combinations wherein the two or more drugsbeing administered act in different manners or in different phased ofthe cell cycle, and/or where the two or more drugs have overlappingtoxicities or side effects, and/or where the drugs being combined eachhas a demonstrated efficacy in treating the particular disease statemanifested by the patient.

Accordingly, a compound of Formula (I) may be administered incombination with other anti-cancer treatments useful in the treatment ofcancer or other proliferative diseases. The invention herein furthercomprises use of a compound of Formula (I) in preparing medicaments forthe treatment of cancer, and/or it comprises the packaging of a compoundof Formula (I) herein together with instructions that the compound beused in combination with other anti-cancer or cytotoxic agents andtreatments for the treatment of cancer. The present invention furthercomprises combinations of a compound of Formula (I) and one or moreadditional agents in kit form, e.g., where they are packaged together orplaced in separate packages to be sold together as a kit, or where theyare packaged to be formulated together.

The compound of Formula (I) can be formulated or co-administered withother therapeutic agents that are selected for their particularusefulness in addressing side effects associated with the aforementionedconditions. For example, the compound of Formula (I) may be formulatedwith agents to prevent nausea, hypersensitivity and gastric irritation,such as antiemetics, and H₁ and H₂ antihistaminics.

The phrase “anti-cancer treatment” includes but is not limited to, forexample, radiation therapy and surgery.

The other anti-cancer agents may be selected from any one or more of thefollowing: alkylating agents (including nitrogen mustards, alkylsulfonates, nitrosoureas, ethylenimine derivatives, and triazenes);anti-angiogenics (including matrix metalloproteinase inhibitors);antimetabolites (including adenosine deaminase inhibitors, folic acidantagonists, purine analogues, and pyrimidine analogues); antibiotics orantibodies (including monoclonal antibodies, CTLA-4 antibodies,anthracyclines); aromatase inhibitors; cell-cycle response modifiers;enzymes; farnesyl-protein transferase inhibitors; hormonal andantihormonal agents and steroids (including synthetic analogs,glucocorticoids, estrogens/anti-estrogens [e.g., SERMs],androgens/anti-androgens, progestins, progesterone receptor agonists,and luteinizing hormone-releasing [LHRH] agonists and antagonists);insulin-like growth factor (IGF)/insulin-like growth factor receptor(IGFR) system modulators (including IGFR1 inhibitors);integrin-signaling inhibitors; kinase inhibitors (including multi-kinaseinhibitors and/or inhibitors of Src kinase or Src/abl, cyclin dependentkinase [CDK] inhibitors, panHer, Her-1 and Her-2 antibodies, VEGFinhibitors, including anti-VEGF antibodies, EGFR inhibitors,mitogen-activated protein [MAP] inhibitors, MEK inhibitors, Aurorakinase inhibitors, PDGF inhibitors, and other tyrosine kinase inhibitorsor serine/threonine kinase inhibitors; microtubule-disruptor agents,such as ecteinascidins or their analogs and derivatives;microtubule-stabilizing agents such as taxanes, and thenaturally-occurring epothilones and their synthetic and semi-syntheticanalogs; microtubule-binding, destabilizing agents (including vincaalkaloids); topoisomerase inhibitors; prenyl-protein transferaseinhibitors; platinum coordination complexes; signal transductioninhibitors; and other agents used as anti-cancer and cytotoxic agentssuch as biological response modifiers, growth factors, and immunemodulators.

The above other therapeutic agents, when employed in combination with acompound of Formula (I), can be used, for example, in those amountsindicated in the Physicians' Desk Reference (PDR) or as otherwisedetermined by one of ordinary skill in the art.

In one embodiment, a method is provided for treating cancer comprisingadministering to a mammal in need thereof a compound of Formula (I) or apharmaceutically acceptable salt or prodrug thereof; administering aglucocorticoid; and optionally, one or more additional anticancer agent.Examples of suitable glucocorticoids include, but are not limited to,dexamethasone and prednisolone.

In one embodiment, a method is provided for treating cancer comprisingadministering to a mammal in need thereof a compound of Formula (I) or apharmaceutically acceptable salt or prodrug thereof; administering amineralocorticoid receptor antagonist; and optionally, one or moreadditional anticancer agent. Examples of suitable mineralocorticoidreceptor antagonists include, but are not limited to, eplerenone.

In another embodiment, a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof is used to treat prostate cancer.

In one embodiment, the patient is an animal.

In another embodiment, the patient is a mammalian species including, butnot limited to, for example, humans and domestic animals, such as, forexample, dogs, cats, and horses.

In one embodiment, the present invention provides a compound of Formula(I) or a pharmaceutically acceptable salt thereof for use in therapy.

In one embodiment, the use of a compound of Formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of cancer, including prostate cancer, isprovided.

In one embodiment, the use of a compound of Formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of cancer, including breast cancer, isprovided.

Methods of Preparation

The compounds of the present invention may be prepared by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description provided herein.For illustrative purposes, general Schemes 1 to 20 below show generalmethods for preparing the compounds of the present invention, as well askey intermediates. For a more detailed description of the individualreaction steps, see the Example section below. Those skilled in the artwill appreciate that other synthetic routes may be used to synthesizethe inventive compounds. Although specific starting materials andreagents are depicted in the Schemes and discussed below, other startingmaterials and reagents can easily be substituted to provide a variety ofcompounds of the present invention. In addition, many of the compoundsprepared by the methods below can be further modified in light of thisdisclosure using conventional chemistry well known to those skilled inthe art.

As shown in Scheme 1, for instance, C1-aryl or alkyl substitutedbenzoisoxazoles of type IA can be prepared from3-bromo-2-fluorobenzaldehyde II via a Grignard addition into thealdehyde. The resultant alcohol III can be oxidized, by Dess-Martinperiodinane for example, to afford the ketone of general structure IV.Treatment of the ketone with hydroxylamine can afford oxime V.Subsequently, cyclization to provide the corresponding benzoisoxazole VIwill occur in the presence of a base, such as NaH. Under standard Suzukicoupling conditions, benzoisoxazole VI can be coupled with a boronicester or acid VII to furnish compounds of general structure IA.

The general structure of the aryl boronic ester or acid of type VIIshown in Scheme 1 can be synthesized from the corresponding halide VIIIby a palladium-mediated reaction with a source of boron, such asbis(pinacolato)diboron (Scheme 2). Alternatively halogen-metal exchangewith aryl halide VIII and a subsequent reaction with triisopropyl boratewill also afford boronic esters or acids of type VII.

The general halides of type VIII used in the synthesis of aryl boronicester or acid VII can originate from pyrimidyl ethers X (Scheme 3),pyrimidyl amines XI (Scheme 4), 4-alkyl or 4-aryl pyrimidines XIII(Scheme 5), 4-aryl pyridines XV (Scheme 6), and 4-cycloalkyl XVII or4-alkyl pyridines XVII, XVIII (Scheme 7 and 8). Each of these halidescan be synthesized in the following manner. The pyrimidyl ethers X canbe generated from displacement of the corresponding pyrimidyl chlorideIX with an alcohol and base. The pyrimidyl amines XI can be synthesizedunder the same reaction conditions from the pyrimidyl chloride IX andammonia or a primary or secondary amine. 4-Alkyl and 4-aryl substitutedpyrimidines XIII can be prepared by many methods well known to thoseskilled in the art. Scheme 5 depicts one such method where5-bromopyrimidine XII can be treated with an alkyl or aryl lithium or aGrignard reagent to give the 4-substituted dihydropyrimidine. Subsequentoxidation by, for example, DDQ, then gives the desired 4-substitutedpyrimidine XIII In contrast, 4-aryl pyridines of general structure XVcan be prepared by Suzuki coupling of boronic ester XIV with an aryliodide under palladium catalysis. Substituted pyridines of type XVII andXVIII can be synthesized by deprotonation of 3-bromopyridine with astrong base such as LDA to generate an anion, and then a subsequentreaction with an alkyl or cycloalkyl ketone to give substitutedpyridines of type XVII or treatment with an alkyl iodide to afford4-alkyl pyridines of type XVIII. Finally, the pyrrolopyrimidine XXdepicted in Scheme 9 can be prepared from 5-bromopyrimidine XII.Addition of an alkyllithium reagent to this commercially availablestarting material will give the corresponding 4-substituteddihydropyrimidine XIX. Subsequent oxidation by, for example, DDQ thengives the desired 4-substituted pyrimidine. Treatment of thisintermediate XIX with an organic acid, such as formic acid, willgenerate the corresponding aldehyde. Further reaction of the aldehydewith Burgess reagent will promote cyclization to the desiredpyrrolopyrimidine XX.

The compounds of type IA depicted in Scheme 1 can alternatively besynthesized by a Pd (II) mediated coupling of benzoisoxazole VI with aboron source XXI, such as 4,4,5,5,-tetramethyl-1,3,2-dioxaborolane, toform benzoisoxazole ester or acid XXII (Scheme 10). Reaction ofintermediate XXII with a heteroaryl halide VIII under standard Suzukiconditions can afford analogs of general structure IA.

Preparation of benzoisoxazoles linked to a heteroatom at C3 can beaccomplished by literature methods that are well known to those skilledin the art. Scheme 11 depicts a commonly used method for the preparationof benzoisoxazole IB from commercially available3-bromo-2-fluorobenzonitrile or from 3-fluoro-4-iodopicolinonitrileXXIII, which is available in one step from the iodination of3-fluoropicolinonitrile XXVII (Scheme 12). A standard Suzuki coupling ofthe general aryl halide XXIII with boronic ester or acid VII can affordbiaryls of type XXIV. Subsequently, reaction of this intermediate withN-hydroxyacetamide induces cyclization and formation of benzoisoxazoleamine XXV. Treatment of the primary amine with sodium nitrite andhydrochloric acid can provide the corresponding benzoisoxazole chlorideXXVI. Finally, displacement of the aryl chloride with an alcohol, thiolor amine in the presence of a base will afford analogs of generalstructure IB.

Another method of generating benzonitrile XXIV utilized in Scheme 11,when X═C, can be achieved by a standard Suzuki reaction betweenheteroaryl halide VIII and commercially available boronic ester or acidXXVIII (Scheme 13).

Additionally, if aryl, heteroaryl, alkyl, or cycloalkyl groups aredesired at C3 of the general structure IA or IC, those skilled in theart can prepare such compounds from intermediate XXIV (Scheme 14). AGrignard addition into the nitrile and a subsequent hydrolysis of the insitu generated imine with HCl can provide ketone XXIX. Further reactionof intermediate XXIX with hydroxylamine will afford oxime XXX, which canbe cyclized to the corresponding benzoisoxazole of general structure IAor IC in the presence of a base, such as NaH.

Furthermore, benzoisoxazoles linked to a variety of substitutedpyrimidines of general structure IA, IB, or IC can be synthesized fromcompounds of general structure XXXI (Scheme 15). Treatment of compoundXXXI with peroxyacetic acid and sulfuric acid can provide hydroxylatedintermediate XXXII. Reaction of the pyrimidinol with phosphorusoxychloride will furnish chloropyrimidine XXXIII Finally, displacementof the chloride with an alcohol or amine can lead to compounds ofgeneral structure IA, IB, or IC.

Those skilled in the art will also find that substituted pyrimidineslinked to benzoisoxazoles of general structure IA or IC can besynthesized from biaryl intermediate XXXIV (Scheme 16). Similar to thereaction sequence shown in Scheme 15, treatment of the pyrimidine withperoxyacetic acid and sulfuric acid will give pyrimidinol XXXV.Subsequently, a Grignard addition into the nitrile followed byhydrolysis with hydrochloric acid can lead to a variety of substitutedketones of type XXXVI. Reaction of this ketone with hydroxylamine willfurnish oxime XXXVII. As previously described, cyclization to thecorresponding benzoisoxazole can be accomplished with base. Conversionof the pyrimidinol XXXII to the chloropyrimidine XXXIII can occur byreaction with phosphorus oxychloride. Lastly, displacement of thechloride with an alcohol or amine can lead to compounds of generalstructure IA or IC.

Benzothiophenes or thienopyridines of general structure IE can besynthesized from the commercially available alcohol XXXVIII (Scheme 17).Halogenation of this starting material with phosphorus oxychloride orbromide can provide an intermediate of type XXXIX. Following a standardSuzuki coupling of (hetero)aryl halide XXXIX with a general boronicester or acid VII, an analog of type XXXX can be formed.Functionalization at C3 can be accomplished by a bromination step andthen a Pd(0)-mediated Stille coupling of intermediate XXXXI withstannane XXXXII to give compounds of general structure IE.

Alternatively, compounds of general structure IE can also be synthesizedvia a standard Suzuki coupling of intermediate XXXXI with boronic esteror acid XXXXIII (Scheme 18).

Benzothiophenes of general structure IF can be synthesized frombenzo[b]thiophen-4-amine XXXXIIII (Scheme 19). Treatment of thiscommercially available starting material with methanesulfonyl chloridewill afford sulfonamide XXXXV. Iodination of this intermediate with 12in pyridine will provide the aryl iodide XXXXIV. Subsequently, astandard Suzuki coupling of this compound with a boronic ester or acidVII can furnish analogs of general structure IF.

Benzoisoxazoles of general structure IG can be synthesized from2-amino-6-fluorobenzonitrile XXXXVII (Scheme 20). Iodination of thiscommercially available starting material with a reagent, such as ICl,will provide aryl iodide XXXXVIII. Reaction of the primary amine withmethanesulfonyl chloride and pyridine will give sulfonamide XXXXIX.Following ring closure to benzoisoxazole XXXXX by reaction ofintermediate XXXXIX with N-hydroxyacetamide, a standard Suzuki couplingof benzoisoxazole XXXXX with boronic ester or acid VII can lead tocompounds of general structure IG.

EXAMPLES

The invention is further defined in the following Examples. It should beunderstood that the Examples are given by way of illustration only. Fromthe above discussion and the Examples, one skilled in the art canascertain the essential characteristics of the invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications to adapt the invention to various uses and conditions.As a result, the invention is not limited by the illustrative examplesset forth hereinbelow, but rather defined by the claims appended hereto.

ABBREVIATIONS

-   AcOH acetic acid-   Ac₂O acetic anhydride-   aq. aqueous-   CH₂Cl₂ dichloromethane-   DCE dichloroethane-   DCM dichloromethane-   DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone-   DMAP dimethylaminopyridine-   DIEA diisopropylethylamine-   DME dimethyl ether-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   Et ethyl-   Et₂O diethyl ethyl-   EtOAc ethyl acetate-   EtOH ethanol-   Et₃N triethyl amine-   Et₃SiH trifluorosilane-   g gram(s)-   h or hr hour-   HCl hydrochloric acid-   HPLC high performance liquid chromatography-   iPr isopropyl-   iPrOH isopropanol-   L liter-   LC/MS liquid chromatography/mass spectrometry-   LDA lithium diisopropylamine-   LTMP lithium 2,2,6,6-tetramethylpiperidine-   Me methyl-   MeOH methanol-   mg milligram(s).-   min minute-   mL milliliter-   mmol millimole(s).-   mp melting point-   mol moles-   MS mass spectrometry-   NBS N-bromosuccinimide-   n-BuLi n-butyl lithium-   NaOMe sodium methoxide-   PdCl₂(dppf)-CH₂Cl₂    dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)    dichloromethane adduct-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium-   PMe₃ trimethyl phosphine-   Prep HPLC preparative reverse phase HPLC-   ret. T HPLC retention time (minutes).-   RT or rt room temperature-   sat or sat'd saturated-   TBSCl tert-butyldimethylsilylchloride-   TFA trifluoroacetic acid-   Tf₂O trifluoromethylsulfonic anhydride-   THF tetrahydrofuran-   TLC thin layer chromatography-   VCD vibrational circular dichroism-   μL microliter    HPLC Conditions:

A: Column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45°C.; Gradient: 0-100% B over 4 minutes, then a 1-minute hold at 100% B;Flow: 4 mL/min.

B: SUPELCO® Ascentis Express C18, 4.6×50 mm, 2.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; MobilePhase B: 90:10 acetonitrile:water with 10 mM ammonium acetate;Temperature: 35° C.; Gradient: 0-100% B over 4 minutes, then a 1-minutehold at 100% B; Flow: 4 mL/min.

C: YMC S5 ODS column, 4.6×50 mm. 4 min gradient (0-100% B), 4 mL/min,40° C. @ 220 nm, solvent A: 0.2% H₃PO₄ in 10% MeOH-90% H₂O, solvent B:0.2% H₃PO₄ in 90% MeOH-10% H₂O.

D: SUPELCO® Ascentis Express C18, 4.6×50 mm, 2.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 35° C.; Gradient: 0-100% B over 4 minutes, then a 1-minutehold at 100% B; Flow: 4 mL/min.

E: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; MobilePhase B: 90:10 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.11 mL/min.

LC/MS Conditions:

F: Column: Luna C18 4.6×30 mm 3 u A: 10:90 H₂O:ACN NH₄OAc/B: 10:90H₂O:ACN NH₄OAc; 0%-95% B in 2 min; 4 mL/min flow

G: PHENOMENEX®-Luna 4.6×30 mm S10, 4 minute gradient time, flow rate:4.0 mL/min, Solvent A: 10% MeOH/90% water/0.1% TFA; Solvent B: 90%MeOH/10% water/0.1% TFA, wavelength 220 nm.

H: PHENOMENEX® Luna C18, 50×2, 3μ, 4 minute gradient time, flow rate:0.8 mL/min, Solvent A: 10% MeOH/90% water/10 mM Ammonium Acetate;Solvent B: 90% MeOH/10% water/10 mM ammonium acetate, wavelength 220 nm.

Example 1 7-(4-Methylpyridin-3-yl)-3-phenylbenzo[d]isoxazole

Preparation 1A: (3-Bromo-2-fluorophenyl)(phenyl)methanol

To a solution of 3-bromo-2-fluorobenzaldehyde (0.150 g, 0.739 mmol) inTHF (3.21 mL) cooled to −78° C. was added phenylmagnesium bromide (0.887mL, 0.887 mmol). The reaction mixture was maintained at −78° C. for atleast 1 hr and then allowed to warm to room temperature slowly over 3hr. The reaction was quenched with a saturated aqueous solution ofNH₄Cl. The reaction mixture was diluted with CH₂Cl₂ and the layers wereseparated. The aqueous phase was extracted twice with CH₂Cl₂. Theorganic layers were combined, dried over Na₂SO₄, filtered, andconcentrated to afford the title compound as a colorless residue.

Preparation 1B: (3-Bromo-2-fluorophenyl)(phenyl)methanone

To a solution of Preparation 1A (205 mg, 0.729 mmol) in wet CH₂Cl₂ (2917μL) was added Dess-Martin periodinane (650 mg, 1.531 mmol) at roomtemperature. After 5.5 hr, the reaction was quenched with a 1:1 solutionof saturated aqueous NaHCO₃:10% (w/w) aqueous Na₂S₂O₃. The reactionmixture was diluted with additional CH₂Cl₂ and the resulting mixture wasstirred until both layers became clear. The layers were separated andthe organic phase washed with saturated aqueous NaHCO₃. The aqueousphase was extracted twice with CH₂Cl₂. The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford the titlecompound as a colorless residue.

Preparation 1C: (Z)-(3-Bromo-2-fluorophenyl)(phenyl)methanone oxime

A solution of Preparation 1B (0.204 g, 0.731 mmol) and hydroxylaminehydrochloride (0.345 g, 4.97 mmol) in pyridine (1.700 mL) was refluxedfor 5 hr, allowed to cool to room temperature, and then concentrated invacuo. The crude material was partitioned between EtOAc and 1N HCl. Thelayers were separated and the aqueous phase extracted with EtOAc (3×).Organics combined, dried over Na₂SO₄, filtered, and concentrated toafford the title compound as a yellow solid.

Preparation 1D: 7-Bromo-3-phenylbenzo[d]isoxazole

To a suspension of sodium hydride (0.050 g, 1.243 mmol) in THF (1.880mL) was added dropwise Preparation 1C (0.215 g, 0.731 mmol) in DMF (500μL). The syringe was rinsed with additional DMF (500 μL) into thereaction vial. The reaction mixture was heated at 70° C. for 2.25 hr,then allowed to cool to room temperature. The reaction was quenched withH₂O. The reaction mixture was extracted with EtOAc (3×). The organicphases were combined, dried over Na₂SO₄, filtered, concentrated, andfurther dried under high vacuum to afford a yellow solid. The crudematerial was dissolved in a minimal amount of CH₂Cl₂. Purification ofthe crude material by silica gel chromatography using an ISCO machine(40 g column, 40 mL/min, 0-30% EtOAc in hexanes over 18 min, t_(r)=11min) gave the title compound (140 mg, 0.511 mmol, 69.9% yield) as awhite crystalline solid. LC/MS: Example 1D @ 1.70 (RT) (Condition F). MS(ES): m/z=276.0 [M+H]⁺.

Example 1

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (3.58 mg, 3.10 μmol),Preparation 1D (17.0 mg, 0.062 mmol), sodium carbonate (26.3 mg, 0.248mmol), and 4-methylpyridin-3-ylboronic acid (8.92 mg, 0.065 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(231 μL), EtOH (116 μL), and water (116 μL) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 19 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (7.8 mg, 44%). ESI MS (M+H)⁺=287.1. HPLC Peakt_(r)=2.62 minutes. Purity=99%. HPLC Conditions: A.

Example 2 7-(4-Methoxypyridin-3-yl)-3-phenylbenzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (10.03 mg, 8.68 μmol),Preparation 1D (47.6 mg, 0.174 mmol), sodium carbonate (92 mg, 0.868mmol), and 4-methoxypyridin-3-ylboronic acid, HCl (99 mg, 0.521 mmol).The mixture was stirred at room temperature for 10 min under N₂, thenDME (648 μL), EtOH (324 μL), and water (324 μL) were added sequentially.The resultant mixture was heated at 90° C. overnight. After 24 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a yellow residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (2.1 mg, 3.9% yield). ESI MS (M+H)⁺=303.2.HPLC Peak t_(r)=2.39 minutes. Purity=97%. HPLC Conditions: A.

Example 3 7-(4-Chloropyridin-3-yl)-3-phenylbenzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.90 mg, 5.11 μmol),Preparation 1D (28 mg, 0.102 mmol), sodium carbonate (43.3 mg, 0.409mmol), and4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (73.4mg, 0.306 mmol). The mixture was stirred at room temperature for 10 minunder N₂, then DME (381 μL), EtOH (191 μL), and water (191 μL) wereadded sequentially. The resultant mixture was heated at 90° C.overnight. After 19 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a yellow residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (7.5 mg, 24% yield). ESI MS(M+H)⁺=306.9. HPLC Peak t_(r)=2.75 minutes. Purity=99%. HPLC Conditions:A.

Example 4 7-(4-Methylpyrimidin-5-yl)-3-phenylbenzo[d]isoxazole

Preparation 4A:4-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

Nitrogen was bubbled into a mixture of 5-bromo-4-methylpyrimidine (0.100g, 0.578 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.191 g,0.751 mmol), and potassium acetate (0.129 g, 1.316 mmol) in DMSO (2.89mL) for 10 min. Then1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.019 g, 0.024 mmol) was added and the reactionmixture was heated at 90° C. overnight. The reaction was quenched withH₂O. The reaction mixture was extracted with EtOAc (3×). The organicphases were combined, dried over Na₂SO₄, filtered, and concentrated toafford the title compound (127 mg, 100%) as a dark brown residue.

Example 4

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.69 mg, 4.92 μmol),Preparation 1D (27 mg, 0.098 mmol), sodium carbonate (41.8 mg, 0.394mmol), and Preparation 4A (65.0 mg, 0.295 mmol). The mixture was stirredat room temperature for 10 min under N₂, then DME (368 μL), EtOH (184μL), and water (184 μL) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 19 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a dark brown residue. The crude material waspurified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: WatersXBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: Waters XBridge C18, 19×250 mm,5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford the titlecompounds (2.1 mg, 7.4% yield). ESI MS (M+H)⁺=288.0. HPLC Peakt_(r)=2.31 minutes. Purity >99%. HPLC Conditions: A.

Example 5 7-(Isoquinolin-4-yl)-3-phenylbenzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 1D (27.4 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(26.8 mg, 0.105 mmol). The mixture was stirred at room temperature for10 min under N₂, then DME (373 μL), EtOH (187 μL), and water (187 μL)were added sequentially. The resultant mixture was heated at 90° C.overnight. After 24 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford an orange residue. Thecrude material was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (12 g column, 30 mL/min, 0-50%EtOAc in hexanes over 18 min, tr=9 min) gave7-(isoquinolin-4-yl)-3-phenylbenzo[d]isoxazole (9.5 mg, 0.029 mmol,29.5% yield) as a yellow residue. The crude material was furtherpurified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: WatersXBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: Waters XBridge C18, 19×250 mm,5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 0-60%B over 25 minutes, then a 15-minute hold at 60% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (9.5 mg, 30%). ESIMS (M+H)⁺=323.1. HPLC Peak t_(r)=2.88 minutes. Purity >99%. HPLCConditions: A.

Example 6 3-(4-Fluorophenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

Preparation 6A: (3-Bromo-2-fluorophenyl)(4-fluorophenyl)methanol

To a solution of 3-bromo-2-fluorobenzaldehyde (0.150 g, 0.739 mmol) inTHF (3.21 mL) cooled to −78° C. was added (4-fluorophenyl)magnesiumbromide (0.443 mL, 0.887 mmol). The reaction mixture was maintained at−78° C. for at least 1 hr, then allowed to warm to room temperatureslowly over 2 hr. The reaction was quenched with a saturated aqueoussolution of NH₄Cl. The reaction mixture was diluted with CH₂Cl₂ and thelayers were separated. The aqueous phase was extracted with CH₂Cl₂ (2×).Organics were combined, dried over Na₂SO₄, filtered, and concentrated toafford the title compound as a yellow residue.

Preparation 6B: (3-Bromo-2-fluorophenyl)(4-fluorophenyl)methanone

To a solution of Preparation 6A (0.221 g, 0.739 mmol) in wet CH₂Cl₂(2.96 mL) was added Dess-Martin periodinane (0.658 g, 1.552 mmol) atroom temperature. After 1.75 hr, the reaction was quenched with a 1:1solution of saturated aqueous NaHCO₃: 10% (w/w) aqueous Na₂S₂O₃. Thereaction mixture was diluted with additional CH₂Cl₂. The mixture wasstirred until both layers became clear. The layers were separated andthe aqueous phase extracted with CH₂Cl₂ (2×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford thetitle compound as a yellow residue.

Preparation 6C: (Z)-(3-Bromo-2-fluorophenyl)(4-fluorophenyl)methanoneoxime

A solution of Preparation 6B (0.220 g, 0.741 mmol) and hydroxylaminehydrochloride (0.350 g, 5.04 mmol) in pyridine (1.722 mL) was refluxedfor 1.5 hr, allowed to cool to room temperature, then concentrated invacuo. The crude material was partitioned between EtOAc and 1N HCl. Thelayers were separated and the aqueous phase extracted with EtOAc (3×).The organics were combined, dried over Na₂SO₄, filtered, andconcentrated to afford(Z)-(3-bromo-2-fluorophenyl)(4-fluorophenyl)methanone oxime (231 mg,0.740 mmol, 100% yield) as an orange residue. LC/MS: Example 5C @ 1.50(RT) (Condition A). MS (ES): m/z=312.0 [M+H]⁺.

Preparation 6D: 7-Bromo-3-(4-fluorophenyl)benzo[d]isoxazole

To a suspension of sodium hydride (0.050 g, 1.258 mmol) in THF (9.52 mL)was added dropwise Preparation 6C (0.231 g, 0.740 mmol) in DMF (2.6 mL).The syringe was rinsed with additional DMF (2.6 mL) into the reactionvial. The reaction mixture was heated at 70° C. for 2.5 hr, then allowedto cool to room temperature. The reaction was quenched with H₂O. Thereaction mixture was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, concentrated, and further driedunder high vacuum to afford a yellow solid. The crude material wasdissolved in a minimal amount of CH₂Cl₂. Purification of the crudematerial by silica gel chromatography using an ISCO machine (40 gcolumn, 40 mL/min, 0-30% EtOAc in hexanes over 25 min, t_(r)=9 min) gavethe title compound (162 mg, 0.555 mmol, 74.9% yield) as a whitecrystalline solid.

Example 6 3-(4-Fluorophenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (6.13 mg, 5.31 μmol),Preparation 6D (31 mg, 0.106 mmol), sodium carbonate (45.0 mg, 0.425mmol), and 4-methylpyridin-3-ylboronic acid (15.26 mg, 0.111 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(396 μL), EtOH (198 μL), and water (198 μL) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 24 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (13.0 mg, 40%). ESI MS (M+H)⁺=305.01. HPLCPeak t_(r)=2.67 minutes. Purity >99%. HPLC Conditions: A.

Example 7 7-(4-Chloropyridin-3-yl)-3-(4-fluorophenyl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (6.13 mg, 5.31 μmol),Preparation 6D (31 mg, 0.106 mmol), sodium carbonate (45.0 mg, 0.425mmol), and4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (76 mg,0.318 mmol). The mixture was stirred at room temperature for 10 minunder N₂, then DME (396 μL), EtOH (198 μL), and water (198 μL) wereadded sequentially. The resultant mixture was heated at 90° C.overnight. After 26 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a yellow residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 40-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (6.2 mg, 18%). ESI MS(M+H)⁺=325.0. HPLC Peak t_(r)=2.78 minutes. Purity >99%. HPLCConditions: A.

Example 8 3-(4-Fluorophenyl)-7-(4-methoxypyridin-3-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (7.91 mg, 6.85 μmol),Preparation 6D (40 mg, 0.137 mmol), sodium carbonate (72.6 mg, 0.685mmol), and 4-methoxypyridin-3-ylboronic acid, HCl (78 mg, 0.411 mmol).The mixture was stirred at room temperature for 10 min under N₂, thenDME (511 μL), EtOH (255 μL), and water (255 μL) were added sequentially.The resultant mixture was heated at 90° C. overnight. After 24 hr, thereaction mixture was allowed to cool to room temperature. Then, thereaction was quenched with water. The reaction mixture was diluted withEtOAc. The layers were separated and the aqueous phase was extractedwith EtOAc (3×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a yellow residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-100% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05%TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient:5-85% B over 25 minutes, then a 5-minute hold at 85% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (1.7 mg, 3.9%). ESIMS (M+H)⁺=321.2. HPLC Peak t_(r)=2.45 minutes. Purity >99%. HPLCConditions: B.

Example 9 3-(4-Fluorophenyl)-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole

Preparation 9A:3-(4-Fluorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole

A vial was charged with bis(acetonitrile)palladium(II) chloride (3.20mg, 0.012 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(10.12 mg, 0.025 mmol), and Preparation 6D (0.180 g, 0.616 mmol). Thevial was capped with a rubber septum and then evacuated and backfilledwith N₂ (this sequence was carried out a total of 2 times). Dioxane(0.369 mL) was added via syringe, through the septum, followed by theaddition of triethylamine (0.258 mL, 1.849 mmol) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.134 mL, 0.924 mmol) dropwise.The septum was then replaced with a Teflon screw valve, and the vial wassealed. The reaction mixture was heated at 110° C. After 24 hr, thereaction mixture was allowed to cool to room temperature. The reactionmixture was filtered through a disposable fritted funnel and the filtercake washed with CH₂Cl₂. The filtrate was concentrated to afford thetitle compound (209 mg, 100%) as a yellow solid.

Example 9

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 9A (33.9 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 5-bromo-4-methylpyrimidine (18.17 mg, 0.105 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(Ratio: 2.0, Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), andwater (Ratio: 1.000, Volume: 187 μl) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 17.5 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a residue. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (1.9 mg, 6.2%). ESI MS (M+H)⁺=306.1. HPLC Peakt_(r)=2.41 minutes. Purity >99%. HPLC Conditions: B.

Example 10 3-(4-Fluorophenyl)-7-(isoquinolin-4-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 6D (29.2 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(26.8 mg, 0.105 mmol). The mixture was stirred at room temperature for10 min under N₂, then DME (373 μL), EtOH (187 μL), and water (187 μL)were added sequentially. The resultant mixture was heated at 90° C.overnight. After 24 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a brown residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25minutes, then a 10-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: Waters XBridge C18, 19×250 mm,5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 30-100% B over 25 minutes, then a 10-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford the titlecompound (11.1 mg, 33%). ESI MS (M+H)⁺=341.1. HPLC Peak t_(r)=2.91minutes. Purity >99%. HPLC Conditions: A.

Example 117-(4-Cyclopropylpyrimidin-5-yl)-3-(4-fluorophenyl)benzo[d]isoxazole

Preparation 11A: 5-Bromo-4-cyclopropylpyrimidine

To a solution of 5-bromopyrimidine (3 g, 18.87 mmol) in Et₂O (120 mL)and THF (20 ml) was added cyclopropylmagnesium bromide (39.6 mL, 19.81mmol) at 0° C. The resulting white suspension was stirred at roomtemperature for 1 h and quenched with water (0.340 mL, 18.87 mmol)followed by addition of DDQ (4.28 g, 18.87 mmol) in THF (10 ml). Theresulting black mixture was stirred at room temperature overnight. Thereaction mixture was extracted with EtOAc. The aqueous layer wasextracted with EtOAc and the combined organic layer was washed with NaOH(1N) and brine. The crude product was purified by BIOTAGE® (0-15%EtOAc/hexanes, 1.2 L) to afford the title compound (700 mg, 20%) as ayellow solid. ¹H NMR (500 MHz, chloroform-d) δ ppm 8.87 (1 hr, s), 8.66(1 hr, s), 2.40-2.56 (1 hr, m), 1.13-1.32 (4 hr, m).

Example 11

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 9A (33.9 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 11A (20.90 mg, 0.105 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resulting mixturewas heated at 90° C. overnight. After 16 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a residue. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mMammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (4.0 mg, 11%). ESI MS (M+H)⁺=332.1. HPLC Peakt_(r)=2.87 minutes. Purity=95%. HPLC Conditions: B.

Example 123-(4-Fluorophenyl)-7-(4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)benzo[d]isoxazole

Preparation 12A: 5-Iodo-4-(2,2,2-trifluoroethoxy)pyrimidine

To a solution of 2,2,2-trifluoroethanol (0.672 mL, 9.36 mmol) in THF(18.08 mL) was added, portion wise, at 0° C., NaH (0.424 g, 10.61 mmol).The reaction mixture was stirred at 0° C. for 30 min. Then4-chloro-5-iodopyrimidine (1.5 g, 6.24 mmol) was added and the reactionmixture was refluxed for about 1 hr. The reaction mixture was allowed tocool to room temperature, then a saturated aqueous solution of NH₄Cl wasadded. The mixture was diluted with EtOAc and the layers were separated.The aqueous phase was extracted with EtOAc (2×). The combined organicswere washed with brine (1×), dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford the title compound as a yellow solid.ESI MS (M+H)⁺=304.7.

Example 12

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 9A (33.9 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 12A (31.9 mg, 0.105 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 16 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a residue. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mMammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (4.3 mg, 11%). ESI MS (M+H)⁺=390.0. HPLC Peakt_(r)=2.96 minutes. Purity=99%. HPLC Conditions: B.

Example 13 3-(4-Fluorophenyl)-7-(1,7-naphthyridin-5-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 9A (33.9 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 5-bromo-1,7-naphthyridine (21.95 mg, 0.105 mmol). The mixturewas stirred at room temperature for 10 min under N₂, then DME (Ratio:2.0, Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water(Ratio: 1.000, Volume: 187 μl) were added sequentially. The resultantmixture was heated at 90° C. overnight. After 16 hr, the reactionmixture was allowed to cool to room temperature. The reaction wasquenched with water. The reaction mixture was diluted with EtOAc. Thelayers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a residue. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mMammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (1.8 mg, 4.6%). ESI MS (M+H)⁺=342.1. HPLC Peakt_(r)=2.48 minutes. Purity=88%. HPLC Conditions: B.

Example 143-(4-Fluorophenyl)-7-(pyrrolo[1,2-c]pyrimidin-4-yl)benzo[d]isoxazole

Preparation 14A: 4-(2-(1,3-Dioxan-2-yl)ethyl)-5-bromopyrimidine

To a solution of 5-bromopyrimidine (2 g, 12.58 mmol) in Et₂O (40 mL) atroom temperature was slowly added (2-(1,3-dioxan-2-yl)ethylmagnesiumbromide (0.5M, 27.7 mL, 13.84 mmol). After 1 hr, water (2 mL) was addedfollowed by the careful addition of4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (3.14 g,13.84 mmol) as a solution in THF (15 mL). The resulting dark brownsuspension was stirred at room temperature for an additional 24 hr. Theresulting mixture was then diluted with EtOAc and water, the organicswere separated and the remaining aqueous layer was extracted twice more.The separated organic layers were combined and washed with 1N NaOH, thenwashed with brine, dried over sodium sulfate, and concentrated to affordIntermediate 8A (2.62 g, 76% yield). MS (ES): m/z=274.8 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 9.05 (1 hr, s), 8.89 (1 hr, s), 4.62 (1 hr, t,J=4.95 Hz), 3.92-4.04 (2 hr, m), 3.61-3.75 (2 hr, m), 2.83-3.00 (2 hr,m), 1.77-1.98 (4 hr, m).

Preparation 14B: 3-(5-Bromopyrimidin-4-yl)propanal

To a solution of Preparation 14A (0.920 g, 3.37 mmol) in DCE (6.5 mL) at0° C. was slowly added formic acid (6.46 mL, 168 mmol). The system wasequipped with a reflux condenser and was heated to 50° C. for 5 hr. Theresulting solution was allowed to cool to room temperature and thevolatile solvents were removed in vacuo. The system was diluted with DCMand washed 1× with saturated aqueous sodium bicarbonate, then washedwith brine, dried over sodium sulfate and concentrated to afford thetitle compound (724 mg, 100% yield). MS (ES): m/z=216.8 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 9.77 (1 hr, s), 9.03 (1 hr, s), 8.91 (1 hr, s),3.14 (2 hr, t, J=6.60 Hz), 2.96 (3 hr, t, J=6.60 Hz).

Preparation 14C: 4-Bromopyrrolo[1,2-c]pyrimidine

To a solution of Preparation 14B (724 mg, 3.37 mmol) in THF (10 mL) atroom temperature was added Burgess Reagent (964 mg, 4.04 mmol). Thesystem was stirred for 10 minutes, at which time it was concluded to becomplete. Volatile solvents were removed in vacuo. The crude materialwas diluted with DCM and washed 1× with water, then washed with brine,dried over sodium sulfate and concentrated to afford the title compound(664 mg, 100% yield). MS (ES): m/z=198.8 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.17 (1 hr, s), 7.81 (1 hr, dd, J=2.86, 1.32 Hz), 7.61 (1hr, s), 6.95-7.03 (1 hr, m), 6.55 (1 hr, d, J=3.96 Hz).

Example 14

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 9A (33.9 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 14C (20.69 mg, 0.105 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 15.5 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a residue. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mMammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (1.2 mg, 3.6%). ESI MS (M+H)⁺=330.0. HPLC Peakt_(r)=2.84 minutes. Purity >99%. HPLC Conditions: B.

Example 155-(3-(4-Fluorophenyl)benzo[d]isoxazol-7-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine

Preparation 15A: 5-Iodo-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine

To a solution of 4-chloro-5-iodopyrimidine (0.250 g, 1.040 mmol) and2,2,2-trifluoroethanamine (0.216 g, 2.184 mmol) in EtOH (volume: 2.080ml) was added Hunig's Base (0.200 ml, 1.144 mmol). The reaction mixturewas heated in a microwave for 4 hr at 120° C. and then allowed to coolto room temperature. The solvent was evaporated. The crude material wasdissolved in a minimal amount of CH₂Cl₂ to be chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (24 g column, 35 mL/min, 0-90% EtOAc in hexanes over 25min, t_(r)=12 min) gave the title compound (0.188 g, 0.614 mmol, 59.1%yield) as a yellow residue. ESI MS (M+H)⁺=303.9.

Example 15

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 9A (33.9 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 15A (26.9 mg, 0.105 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 17.5 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a residue. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (2.0 mg, 4.7%). ESI MS (M+H)⁺=389.1. HPLC Peakt_(r)=2.59 minutes. Purity=92%. HPLC Conditions: B.

Example 163-(4-Fluorophenyl)-7-(4-morpholinopyrimidin-5-yl)benzo[d]isoxazole

Preparation 16A: 4-(5-Iodopyrimidin-4-yl)morpholine

To a vial containing a solution of 4-chloro-5-iodopyrimidine (0.200 g,0.832 mmol) in DMF (1.333 mL) was added morpholine (0.291 mL, 3.33 mmol)followed by cesium carbonate (0.542 g, 1.664 mmol). The vial was sealedwith a Teflon cap and heated at 90° C. for 80 min, then allowed to coolto room temperature. The reaction mixture was filtered through adisposable fritted funnel and the filter cake washed with CH₂Cl₂. Thefiltrate was concentrated, then further dried under high vacuum toafford the title compound (235 mg, 97%). ESI MS (M+H)⁺=292.0.

Example 16

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 9A (33.9 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 16A (30.6 mg, 0.105 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 16 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a residue. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 20-55% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (5.0 mg, 13%). ESI MS (M+H)⁺=377.1. HPLC Peakt_(r)=2.37 minutes. Purity=99%. HPLC Conditions: B.

Example 17 7-(4-Methylpyridin-3-yl)-3-(pyridin-2-yl)benzo[d]isoxazole

Preparation 17A: (3-Bromo-2-fluorophenyl)(pyridin-2-yl)methanol

To a solution of 3-bromo-2-fluorobenzaldehyde (0.250 g, 1.231 mmol) inTHF (5.35 mL) cooled to −78° C. was added pyridin-2-ylmagnesium bromide(5.91 mL, 1.478 mmol). The reaction mixture was maintained at −78° C.for at least 1 hr, then allowed to warm to room temperature slowly over2 hr. The reaction quenched with a saturated aqueous solution of NH₄Cl.The reaction mixture was diluted with CH₂Cl₂. Layers were separated. Theaqueous phase was extracted with CH₂Cl₂ (2×). The organics werecombined, dried over Na₂SO₄, filtered, and concentrated to afford ayellow residue. The crude material was dissolved in a minimal amountCH₂Cl₂ and chromatographed. Purification of the crude material by silicagel chromatography using an ISCO machine (40 g column, 40 mL/min, 1-40%EtOAc in hexanes over 25 min, t_(r)=16 min) gave the title compound (78mg, 0.276 mmol, 22.45% yield) as a yellow residue.

Preparation 17B: (3-Bromo-2-fluorophenyl)(pyridin-2-yl)methanone

To a solution of Preparation 17A (0.0784 g, 0.278 mmol) in wet CH₂Cl₂(1.112 mL) was added Dess-Martin periodinane (0.248 g, 0.584 mmol) atroom temperature. After 5.5 hr, the reaction was quenched with a 1:1solution of saturated aqueous NaHCO₃: 10% (w/w) aqueous Na₂S₂O₃. Thereaction mixture was diluted with additional CH₂Cl₂ and stirred untilboth layers became clear. The layers were separated and the organicphase washed with saturated aqueous NaHCO₃. The aqueous phase wasextracted with CH₂Cl₂ (2×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford the title compound (78 mg,0.278 mmol, 100% yield) as a pink solid.

Preparation 17C: (E)-(3-Bromo-2-fluorophenyl)(pyridin-2-yl)methanoneoxime

A solution of Preparation 17B (78.7 mg, 0.281 mmol) and hydroxylaminehydrochloride (133 mg, 1.911 mmol) in pyridine (653 μL) was refluxed for2 hr, allowed to cool to room temperature, and then concentrated invacuo. The crude material was partitioned between EtOAc and 1N HCl. Thelayers were separated and the aqueous phase extracted with EtOAc (5×).The organics were combined, dried over Na₂SO₄, filtered, andconcentrated to afford the title compound (80.4 mg, 0.272 mmol, 97%yield) as a yellow residue.

Preparation 17D: 7-Bromo-3-(pyridin-2-yl)benzo[d]isoxazole

To a suspension of sodium hydride (0.037 g, 0.927 mmol) in THF (1.403mL) was added dropwise Preparation 17C (0.161 g, 0.546 mmol) in DMF(0.779 mL). The syringe was rinsed with additional DMF (0.779 mL) intothe reaction vial. The reaction mixture was heated at 70° C. for 2 hr,and then allowed to cool to room temperature. The reaction was quenchedwith H₂O. The mixture was extracted with EtOAc (3×). The organic phaseswere combined, dried over Na₂SO₄, filtered, concentrated, and furtherdried under high vacuum to afford a brown residue. The crude materialwas dissolved in a minimal amount of CH₂Cl₂ to be chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (24 g column, 35 mL/min, 0-20% EtOAc in hexanes over 15min, t_(r)=8.5 min) gave the title compound (96 mg, 0.349 mmol, 64.0%yield) as a white solid.

Example 17

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.04 mg, 4.36 μmol),Preparation 17D (24 mg, 0.087 mmol), sodium carbonate (37.0 mg, 0.349mmol), and 4-methylpyridin-3-ylboronic acid (12.54 mg, 0.092 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(326 μL), EtOH (163 μL), and water (163 μL) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 24 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The mixture was diluted with EtOAc. The layerswere separated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (12.7 mg, 51%). ESI MS (M+H)⁺=288.0. HPLC Peakt_(r)=2.38 minutes. Purity >99%. HPLC Conditions: A.

Example 18 7-(4-Chloropyridin-3-yl)-3-(pyridin-2-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.88 mg, 5.09 μmol),Preparation 17D (28 mg, 0.102 mmol), sodium carbonate (43.2 mg, 0.407mmol), and4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (73.1mg, 0.305 mmol). The mixture was stirred at room temperature for 10 minunder N₂, then DME (380 μL), EtOH (190 μL), and water (190 μL) wereadded sequentially. The resultant mixture was heated at 90° C.overnight. After 25 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a yellow solid. Thecrude material was dissolved in a minimal amount of CH₂Cl₂ andchromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (12 g column, 35 mL/min, 1-30% MeOHin CH₂Cl₂ over 19 min, t_(r)=11 min) gave the title compound (5.5 mg,0.018 mmol, 17.21% yield) as a white solid. ESI MS (M+H)⁺=308.1. HPLCPeak t_(r)=3.315 minutes. Purity=98%. HPLC Conditions: C.

Example 19 7-(Isoquinolin-4-yl)-3-(pyridin-2-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (6.72 mg, 5.82 μmol),Preparation 17D (0.032 g, 0.116 mmol), sodium carbonate (0.049 g, 0.465mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(0.031 g, 0.122 mmol). The mixture was stirred at room temperature for10 min under N₂, then DME (0.434 mL), EtOH (0.217 mL), and water (0.217mL) were added sequentially. The resultant mixture was heated at 90° C.overnight. After 14 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a dark red residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (17.7 mg, 47%). ESIMS (M+H)⁺=324.1. HPLC Peak t_(r)=2.71 minutes. Purity >99%. HPLCConditions: B.

Example 20 7-(4-Methylpyridin-3-yl)-3-(thiazol-2-yl)benzo[d]isoxazole

Preparation 20A: (3-Bromo-2-fluorophenyl)(thiazol-2-yl)methanol

To a solution of 2-bromothiazole (0.088 mL, 0.985 mmol) in THF (2.99 mL)cooled to 0° C. was added isopropylmagnesium chloride (0.493 mL, 0.985mmol). After 50 min, 3-bromo-2-fluorobenzaldehyde (0.200 g, 0.985 mmol)was added. The reaction mixture was allowed to warm to room temperatureovernight. After 12 hr, the reaction was quenched with saturated aqueousNH₄Cl. The reaction mixture was diluted with CH₂Cl₂. The layers wereseparated. The aqueous phase was extracted with CH₂Cl₂ (2×). The organicphases were combined, dried over Na₂SO₄, filtered, and concentrated toafford the title compound as a brown liquid.

Preparation 20B: (3-Bromo-2-fluorophenyl)(thiazol-2-yl)methanone

To a solution of Preparation 20A (0.284 g, 0.986 mmol) in wet CH₂Cl₂(3.94 mL) was added Dess-Martin periodinane (1.045 g, 2.464 mmol) atroom temperature. After 2.5 hr, the reaction was quenched with a 1:1solution of saturated aqueous NaHCO₃: 10% (w/w) aqueous Na₂S₂O₃. Thereaction mixture was diluted with additional CH₂Cl₂. The mixture wasstirred until both layers became clear. The layers were separated andthe organic phase washed with saturated aqueous NaHCO₃. The aqueousphase was extracted with CH₂Cl₂ (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated, and further dried underhigh vacuum to afford a residue. The crude material was dissolved in aminimal amount of CH₂Cl₂ to be chromatographed. Purification of thecrude material by silica gel chromatography using an ISCO machine (40 gcolumn, 40 mL/min, 0-15% MeOH in CH₂Cl₂ over 15 min, t_(r)=2.5 min) gavethe title compound (158 mg, 0.552 mmol, 56.0% yield) (2 steps) as awhite solid.

Preparation 20C: (E)-(3-Bromo-2-fluorophenyl)(thiazol-2-yl)methanoneoxime

A solution of Preparation 20B (0.141 g, 0.493 mmol) and hydroxylaminehydrochloride (0.233 g, 3.35 mmol) in pyridine (1.5 mL) was refluxed for1.5 hr, allowed to cool to room temperature, and then concentrated invacuo. The crude material was partitioned between EtOAc and 1N HCl. Thelayers were separated and the aqueous phase extracted with EtOAc (5×).The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford the title compound (148 mg, 0.491 mmol, 100%yield) as a yellow residue.

Preparation 20D: 7-Bromo-3-(thiazol-2-yl)benzo[d]isoxazole

To a suspension of sodium hydride (0.033 g, 0.830 mmol) in THF (1.255mL) was added dropwise Preparation 20C (0.147 g, 0.488 mmol) in DMF(0.697 mL). The reaction mixture was heated at 70° C. for 2.5 hr, thenallowed to cool to room temperature. The reaction was quenched with H₂O.The reaction mixture was extracted with EtOAc (3×). The organic phaseswere combined, dried over Na₂SO₄, filtered, concentrated, and furtherdried under high vacuum to afford a yellow residue. The crude materialwas dissolved in a minimal amount of CH₂Cl₂ to be chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (24 g column, 35 mL/min, 0-50% EtOAc in hexanes over 18min, t_(r)=6 min) gave the title compound (43 mg, 0.153 mmol, 31.3%yield) as a white solid.

Example 20 7-(4-Methylpyridin-3-yl)-3-(thiazol-2-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (6.58 mg, 5.69 μmol),Preparation 20D (32 mg, 0.114 mmol), sodium carbonate (48.3 mg, 0.455mmol), and 4-methylpyridin-3-ylboronic acid (16.37 mg, 0.120 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(425 μL), EtOH (212 μL), and water (212 μL) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 24 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (15.8 mg, 47%). ESI MS (M+H)⁺=294.1. HPLC Peakt_(r)=2.36 minutes. Purity >99%. HPLC Conditions: A.

Example 21 7-(4-Chloropyridin-3-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole

Preparation 21A: (3-Bromo-2-fluorophenyl)(pyrazin-2-yl)methanol

To a stirring solution of 2-iodopyrazine (0.195 mL, 1.970 mmol) in THF(3.28 mL) at 0° C. was slowly added butyl magnesium chloride (0.985 mL,1.970 mmol). The mixture was allowed to stir for 30 min, then3-bromo-2-fluorobenzaldehyde (0.400 g, 1.970 mmol) was added. After 2hr, the reaction was quenched with a saturated aqueous solution ofNH₄Cl. The reaction mixture was diluted with CH₂Cl₂. The layers wereseparated. The aqueous phase was extracted with CH₂Cl₂ (2×). The organicphases were combined, dried over Na₂SO₄, filtered, and concentrated toafford a yellow residue. The crude material was dissolved in a minimalamount of CH₂Cl₂ to be chromatographed. Purification of the crudematerial by silica gel chromatography using an ISCO machine (40 gcolumn, 40 mL/min, 30-70% EtOAc in hexanes over 19 min, t_(r)=12 min)gave the title compound (347 mg, 1.226 mmol, 62.2% yield) as a yellowresidue.

Preparation 21B (3-Bromo-2-fluorophenyl)(pyrazin-2-yl)methanone

To a solution of Preparation 21A (0.347 g, 1.226 mmol) in wet CH₂Cl₂(4.90 mL) was added Dess-Martin periodinane (1.300 g, 3.06 mmol) at roomtemperature. After 2 hr, the reaction was quenched with a 1:1 solutionof saturated aqueous NaHCO₃: 10% (w/w) aqueous Na₂S₂O₃. The reactionmixture was diluted with additional CH₂Cl₂. The mixture was stirreduntil both layers became clear. The layers were separated and theorganic phase washed with saturated aqueous NaHCO₃. The aqueous phasewas extracted with CH₂Cl₂ (2×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford the title compound(345 mg, 1.227 mmol, 100% yield) as a yellow solid.

Preparation 21C: (E)-(3-Bromo-2-fluorophenyl)(pyrazin-2-yl)methanoneoxime

A solution of Preparation 21B (0.606 g, 2.156 mmol) and hydroxylaminehydrochloride (1.019 g, 14.66 mmol) in pyridine (6.55 mL) was refluxedfor 2 hr, allowed to cool to room temperature, and then concentrated invacuo. The crude material was partitioned between EtOAc and 1N HCl. Thelayers were separated and the aqueous phase extracted with EtOAc (5×).The organics were combined, dried over Na₂SO₄, filtered, andconcentrated to afford the title compound (638 mg, 2.155 mmol, 100%yield) as a yellow residue.

Preparation 21D: 7-Bromo-3-(pyrazin-2-yl)benzo[d]isoxazole

To a suspension of sodium hydride (0.147 g, 3.66 mmol) in THF (5.54 mL)was added dropwise Preparation 21C (0.638 g, 2.155 mmol) in DMF (3.08mL). The reaction mixture was heated at 70° C. for 2 hr, then allowed tocool to room temperature. The reaction was quenched with H₂O. Thereaction mixture was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, concentrated, and further driedunder high vacuum to afford a yellow residue. The crude material wasdissolved in a minimal amount of CH₂Cl₂ to be chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (40 g column, 40 mL/min, 0-80% EtOAc in hexanes over 25min, t_(r)=13 min) gave the title compound (336 mg, 1.217 mmol, 56.5%yield) as a yellow solid.

Example 21

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.86 mg, 5.07 μmol),Preparation 21D (0.028 g, 0.101 mmol), sodium carbonate (0.043 g, 0.406mmol), and4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.073g, 0.304 mmol). The mixture was stirred at room temperature for 10 minunder N₂, then DME (0.378 mL), EtOH (0.189 mL), and water (0.189 mL)were added sequentially. The resultant mixture was heated at 90° C.overnight. After 15 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a brown residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (12.6 mg, 40%). ESI MS(M+H)⁺=309.1. HPLC Peak t_(r)=2.22 minutes. Purity >99%. HPLCConditions: A.

Example 22 7-(4-Methylpyridin-3-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 21D (27.6 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 4-methylpyridin-3-ylboronic acid (14.38 mg, 0.105 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(373 μL), EtOH (187 μL), and water (187 μL) were added sequentially. Theresulting mixture was heated at 90° C. overnight. After 24 hr, thereaction mixture was allowed to cool to room temperature. Then thereaction was quenched with water. The reaction mixture was diluted withEtOAc. The layers were separated and the aqueous phase was extractedwith EtOAc (3×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column:Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 30-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (11.5 mg, 40%). ESI MS(M+H)⁺=289.1. HPLC Peak t_(r)=2.08 minutes. Purity >99%. HPLCConditions: A.

Example 23 7-(Isoquinolin-4-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 21D (27.6 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(26.8 mg, 0.105 mmol). The mixture was stirred at room temperature for10 min under N₂, then DME (373 μL), EtOH (187 μL), and water (187 μL)were added sequentially. The resultant mixture was heated at 90° C.overnight. After 24 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a red-orange residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (19.2 mg, 59%). ESI MS(M+H)⁺=325.1. HPLC Peak t_(r)=2.38 minutes. Purity >99%. HPLCConditions: A.

Example 24 7-(4-Methoxypyridin-3-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (0.012 g, 9.96 μmol),Preparation 21D (0.055 g, 0.199 mmol), sodium carbonate (0.106 g, 0.996mmol), and 4-methoxypyridin-3-ylboronic acid, HCl (0.113 g, 0.598 mmol).The mixture was stirred at room temperature for 10 min under N₂, thenDME (0.743 mL), EtOH (0.372 mL), and water (0.372 mL) were addedsequentially. The resultant mixture was heated at 90° C. overnight.After 24 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a brown residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-60% Bover 25 minutes, then 10-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (5.2 mg, 8.6%). ESIMS (M+H)⁺=305.1. HPLC Peak t_(r)=1.90 minutes. Purity >99%. HPLCConditions: A.

Example 257-(4-Cyclopropylpyrimidin-5-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole

Preparation 25A:3-(Pyrazin-2-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole

A vial was charged with bis(acetonitrile)palladium(II) chloride (1.597mg, 6.16 μmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(5.06 mg, 0.012 mmol), and Preparation 21D (0.085 g, 0.308 mmol). Thevial was capped with a rubber septum and then evacuated and backfilledwith N₂ (this sequence was carried out a total of 2 times). Dioxane(0.184 mL) was added via syringe, through the septum, followed by theaddition of triethylamine (0.129 mL, 0.924 mmol) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.067 mL, 0.462 mmol) dropwise.The septum was then replaced with a Teflon screw valve, and the vial wassealed. The reaction mixture was heated at 110° C. After 15 hr, thereaction mixture was allowed to cool to room temperature. The reactionmixture was filtered through a disposable fritted funnel and the filtercake washed with CH₂Cl₂. The filtrate was concentrated to the titlecompound as a brown residue.

Example 25

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (4.45 mg, 3.85 μmol),Preparation 25A (24.88 mg, 0.077 mmol), sodium carbonate (32.6 mg, 0.308mmol), and 5-bromo-4-cyclopropylpyrimidine (16.09 mg, 0.081 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(Ratio: 2.0, Volume: 287 μl), EtOH (Ratio: 1.000, Volume: 144 μl), andwater (Ratio: 1.000, Volume: 144 μl) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 19 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a residue. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (2.2 mg, 9.0%). ESI MS (M+H)⁺=316.1. HPLC Peakt_(r)=2.28 minutes. Purity >99%. HPLC Conditions: B.

Example 263-(Pyrazin-2-yl)-7-(4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (4.45 mg, 3.85 μmol),Preparation 25A (24.88 mg, 0.077 mmol), sodium carbonate (32.6 mg, 0.308mmol), and Preparation 12A (24.58 mg, 0.081 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 287 μl), EtOH (Ratio: 1.000, Volume: 144 μl), and Water (Ratio:1.000, Volume: 144 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 19 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a residue. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mMammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (2.0 mg, 6.3%). ESI MS (M+H)⁺=374.0. HPLC Peakt_(r)=2.45 minutes. Purity=90%. HPLC Conditions: B.

Example 27 7-(4-Methylpyrimidin-5-yl)-3-(pyrazin-2-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (4.45 mg, 3.85 μmol),Preparation 25A (24.88 mg, 0.077 mmol), sodium carbonate (32.6 mg, 0.308mmol), and 5-bromo-4-methylpyrimidine (13.99 mg, 0.081 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(Ratio: 2.0, Volume: 287 μl), EtOH (Ratio: 1.000, Volume: 144 μl), andwater (Ratio: 1.000, Volume: 144 μl) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 19 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a residue. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 5-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-50% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (1.4 mg, 6.2%). ESIMS (M+H)⁺=290.0. HPLC Peak t_(r)=1.78 minutes. Purity >99%. HPLCConditions: B.

Example 28 3-Cyclopropyl-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

Preparation 28A: (3-Bromo-2-fluorophenyl)(cyclopropyl)methanol

To a solution of 3-bromo-2-fluorobenzaldehyde (0.500 g, 2.463 mmol) inTHF (10.71 mL) cooled to −78° C. was added cyclopropylmagnesium bromide(5.91 mL, 2.96 mmol). The reaction mixture was maintained at −78° C. forat least 2 hr, then allowed to warm to room temperature. During thistime, additional cyclopropylmagnesium bromide (5.91 mL, 2.96 mmol) wasadded. After 30 min, the reaction was quenched with a saturated aqueoussolution of NH₄Cl. The reaction mixture was diluted with CH₂Cl₂. Thelayers were separated and the aqueous phase extracted with CH₂Cl₂ (2×).The organics were combined, dried over Na₂SO₄, filtered, andconcentrated to afford the title compound (0.604 g, 2.464 mmol, 100%yield) as a yellow residue.

Preparation 28B: (3-Bromo-2-fluorophenyl)(cyclopropyl)methanone

To a solution of Preparation 28A (0.604 g, 2.464 mmol) in wet CH₂Cl₂(9.86 mL) was added Dess-Martin periodinane (2.61 g, 6.16 mmol) at roomtemperature. After 2 hr, the reaction was quenched with a 1:1 solutionof saturated aqueous NaHCO₃: 10% (w/w) aqueous Na₂S₂O₃. The reactionmixture was diluted with additional CH₂Cl₂. The mixture was stirreduntil both layers became clear. The layers were separated and theorganic phase washed with saturated aqueous NaHCO₃. The aqueous phasewas extracted with CH₂Cl₂ (2×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford the title compound(0.599 g, 2.464 mmol, 100% yield) as a yellow solid.

Preparation 28C: (Z)-(3-Bromo-2-fluorophenyl)(cyclopropyl)methanoneoxime

A solution of Preparation 28B (0.599 g, 2.464 mmol) and hydroxylaminehydrochloride (1.164 g, 16.76 mmol) in pyridine (7.49 mL) was refluxedfor 2.5 hr, allowed to cool to room temperature, and then concentratedin vacuo. The crude material was partitioned between EtOAc and 1N HCl.The layers were separated and the aqueous phase extracted with EtOAc(5×). Organics combined, dried over Na₂SO₄, filtered, and concentratedto afford the title compound (0.636 g, 2.464 mmol, 100% yield) as ayellow residue.

Preparation 28D: 7-Bromo-3-cyclopropylbenzo[d]isoxazole

To a suspension of sodium hydride (0.168 g, 4.19 mmol) in THF (6.34 mL)was added dropwise Preparation 28C (0.636 g, 2.464 mmol) in DMF (3.52mL). The reaction mixture was heated at 70° C. for 2 hr, then allowed tocool to room temperature. The reaction was quenched with H₂O. Thereaction mixture was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, concentrated, and further driedunder high vacuum to afford an orange residue. The crude material wasdissolved in a minimal amount of CH₂Cl₂ to be chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (40 g column, 40 mL/min, 0-30% EtOAc in hexanes over 19min, t_(r)=6 min) gave the title compound (0.198 g, 0.832 mmol, 33.7%yield) (4 steps) as an orange residue.

Example 28

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (6.07 mg, 5.25 μmol),Preparation 28D (0.025 g, 0.105 mmol), sodium carbonate (0.045 g, 0.420mmol), and 4-methylpyridin-3-ylboronic acid (0.015 g, 0.110 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(0.392 mL), EtOH (0.196 mL), and water (0.196 mL) were addedsequentially. The resultant mixture was heated at 90° C. overnight.After 24 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a brown residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient: 0-100% B over 25 minutes,then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containingthe desired product were combined and dried via centrifugal evaporation.The material was further purified via preparative LC/MS with thefollowing conditions: Column: Waters XBridge C18, 19×250 mm, 5-μmparticles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to afford the title compound (10.1mg, 38%). ESI MS (M+H)⁺=251.2. HPLC Peak t_(r)=2.20 minutes.Purity >99%. HPLC Conditions: A.

Example 29 3-Cyclopropyl-7-(4-methoxypyridin-3-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (6.07 mg, 5.25 μmol),Preparation 28D (0.025 g, 0.105 mmol), sodium carbonate (0.056 g, 0.525mmol), and 4-methoxypyridin-3-ylboronic acid, HCl (0.060 g, 0.315 mmol).The mixture was stirred at room temperature for 10 min under N₂, thenDME (0.392 mL), EtOH (0.196 mL), and water (0.196 mL) were addedsequentially. The resultant mixture was heated at 90° C. overnight.After 23 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a brown residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (2.1 mg, 7.4%). ESI MS(M+H)⁺=267.2. HPLC Peak t_(r)=2.05 minutes. Purity=98%. HPLC Conditions:A.

Example 30 7-(4-Chloropyridin-3-yl)-3-cyclopropylbenzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (6.07 mg, 5.25 μmol),Preparation 28D (0.025 g, 0.105 mmol), sodium carbonate (0.045 g, 0.420mmol), and4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.075g, 0.315 mmol). The mixture was stirred at room temperature for 10 minunder N₂, then DME (0.392 mL), EtOH (0.196 mL), and water (0.196 mL)were added sequentially. The resultant mixture was heated at 90° C.overnight. After 23 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a brown residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (6.9 mg, 24%). ESI MS(M+H)⁺=271.0. HPLC Peak t_(r)=2.32 minutes. Purity >99%. HPLCConditions: B.

Example 313-Cyclopropyl-7-(4-cyclopropylpyrimidin-5-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (2.128 mg, 1.841 μmol),Preparation 28D (10.5 mg, 0.037 mmol), sodium carbonate (15.61 mg, 0.147mmol), and Preparation 11A (7.70 mg, 0.039 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 137 μl), EtOH (Ratio: 1.000, Volume: 68.7 μl), and water (Ratio:1.000, Volume: 68.7 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 15 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a yellow residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (4.0 mg, 39%). ESI MS (M+H)⁺=278.2. HPLC Peakt_(r)=2.38 minutes. Purity >99%. HPLC Conditions: B.

Example 32 3-Cyclopropyl-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole

Preparation 32A:3-Cyclopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole

A vial was charged with bis(acetonitrile)palladium(II) chloride (1.090mg, 4.20 μmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(3.45 mg, 8.40 μmol), and Preparation 28D (0.050 g, 0.210 mmol). Thevial was capped with a rubber septum and then evacuated and backfilledwith N₂ (this sequence was carried out a total of 2 times). Dioxane(0.126 mL) was added via syringe, through the septum, followed by theaddition of triethylamine (0.088 mL, 0.630 mmol) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.046 mL, 0.315 mmol). Theseptum was then replaced with a Teflon screw valve, and the vial sealed.The reaction mixture was heated at 110° C. After 19 hr, the reactionmixture was allowed to cool to room temperature. The reaction mixturewas filtered through a disposable fritted funnel and the filter cakewashed with CH₂Cl₂. The filtrate was concentrated to afford the titlecompound as a brown residue (60 mg, 100%).

Example 32

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (6.08 mg, 5.26 μmol),Preparation 32A (30 mg, 0.105 mmol), sodium carbonate (44.6 mg, 0.421mmol), and 5-bromo-4-methylpyrimidine (19.11 mg, 0.110 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(Ratio: 2.0, Volume: 393 μl), EtOH (Ratio: 1.000, Volume: 196 μl), andwater (Ratio: 1.000, Volume: 196 μl) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 15 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a yellow residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 10-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (6.9 mg, 26%). ESI MS (M+H)⁺=252.1. HPLC Peakt_(r)=1.88 minutes. Purity=99%. HPLC Conditions: B.

Example 33 7-(4-Methylpyridin-3-yl)-3-(pyridazin-3-yl)benzo[d]isoxazole

Preparation 33A: (3-Bromo-2-fluorophenyl)(pyridazin-3-yl)methanol

A solution of LTMP was prepared by reaction of2,2,6,6-tetramethylpiperidine (0.151 mL, 0.896 mmol) in THF (5.6 mL) andn-butyllithium (0.358 mL, 0.896 mmol) at −30° C. and then at 0° C. for30 min.

A solution of pyridazine (0.078 mL, 1.075 mmol) in THF (2.0 mL) and asolution of 3-bromo-2-fluorobenzaldehyde (0.200 g, 0.985 mmol) in THF(2.0 mL) were added simultaneously to a cold solution of LTMP at −78° C.The mixture was stirred at −78° C. for 4 h, followed by the addition ofexcess of HCl/EtOH/THF. The solution was allowed to warm to roomtemperature, then treated with a saturated aqueous solution of NaHCO₃and extracted with CH₂Cl₂ (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford the title compound(0.254 g, 0.897 mmol, 100% yield) as a yellow residue.

Preparation 33B: (3-Bromo-2-fluorophenyl)(pyridazin-3-yl)methanone

To a solution of Preparation 33A (0.254 g, 0.897 mmol) in wet CH₂Cl₂(3.59 mL) was added Dess-Martin periodinane (0.761 g, 1.794 mmol) atroom temperature. After 4 hr, the reaction was quenched with a 1:1solution of saturated aqueous NaHCO₃: 10% (w/w) aqueous Na₂S₂O₃. Thereaction mixture was diluted with additional CH₂Cl₂ and the mixture wasstirred until both layers became clear. The layers were separated andthe organic phase washed with saturated aqueous NaHCO₃. The aqueousphase was extracted with CH₂Cl₂ (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford an orangeresidue. The crude material was dissolved in a minimal amount of CH₂Cl₂to be chromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (40 g column, 40 mL/min, 0-85%EtOAc in hexanes over 25 min, t_(r)=18.5 min) gave the title compound(0.061 g, 0.217 mmol, 24.19% yield) (2 steps) as an orange solid.

Preparation 33C: (E)-(3-Bromo-2-fluorophenyl)(pyridazin-3-yl)methanoneoxime

A solution of Preparation 33B (0.061 g, 0.217 mmol) and hydroxylaminehydrochloride (0.103 g, 1.476 mmol) in pyridine (0.660 mL) was heated at70° C. for 1.5 hr, allowed to cool to room temperature, and thenconcentrated in vacuo. The crude material was partitioned between EtOAcand 1N HCl. The layers were separated and the aqueous phase extractedwith EtOAc (5×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford the title compound (0.043 g, 0.145mmol, 66.9% yield) as a yellow residue.

Preparation 33D: 7-Bromo-3-(pyridazin-3-yl)benzo[d]isoxazole

To a suspension of sodium hydride (9.87 mg, 0.247 mmol) in THF (0.373mL) was added dropwise Preparation 33C (0.043 g, 0.145 mmol) in DMF(0.207 mL). The syringe was rinsed with additional DMF (0.207 mL) intothe reaction vial. The reaction mixture was heated at 70° C. for 2 hr,then allowed to cool to room temperature. The reaction was quenched withH₂O and extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, concentrated, and further dried under highvacuum to afford a yellow residue. The crude material was dissolved in aminimal amount of CH₂Cl₂ to be chromatographed. Purification of thecrude material by silica gel chromatography using an ISCO machine (12 gcolumn, 30 mL/min, 20-60% EtOAc in hexanes over 16 min, t_(r)=9.5 min)gave the title compound (0.030 g, 0.109 mmol, 74.8% yield) as a whitesolid.

Example 33

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (3.14 mg, 2.72 μmol),Preparation 33D (0.015 g, 0.054 mmol), sodium carbonate (0.023 g, 0.217mmol), and 4-methylpyridin-3-ylboronic acid (7.81 mg, 0.057 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(0.203 mL), EtOH (0.101 mL), and water (0.101 mL) were addedsequentially. The resultant mixture was heated at 90° C. overnight.After 24 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a brown residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-55% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (7.6 mg, 49%). ESIMS (M+H)⁺=289.1. HPLC Peak t_(r)=1.86 minutes. Purity >99%. HPLCConditions: B.

Example 34 7-(4-Chloropyridin-3-yl)-3-(pyridazin-3-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (4.81 mg, 4.17 μmol),Preparation 33D (23 mg, 0.083 mmol), sodium carbonate (35.3 mg, 0.333mmol), and4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (59.9mg, 0.250 mmol). The mixture was stirred at room temperature for 10 minunder N₂, then DME (311 μL), EtOH (155 μL), and water (155 μL) wereadded sequentially. The resultant mixture was heated at 90° C.overnight. After 25 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a yellow solid. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 15-50% B over 25 minutes, then a 15-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (3.1 mg, 12%). ESI MS (M+H)⁺=309.0. HPLC Peakt_(r)=1.99 minutes. Purity >99%. HPLC Conditions: B.

Example 353-(5-Fluoro-2-methoxyphenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

Preparation 35A:(3-bromo-2-fluorophenyl)(5-fluoro-2-methoxyphenyl)methanol

To a solution of 3-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF(21.42 mL) cooled to −78° C. was added(5-fluoro-2-methoxyphenyl)magnesium bromide in THF (11.82 mL, 5.91mmol). The reaction mixture was maintained at −78° C. for at least 1 hr,then allowed to warm to room temperature. The reaction mixture was thenre-cooled to 0° C. and additional (5-fluoro-2-methoxyphenyl)magnesiumbromide in THF (11.82 mL, 5.91 mmol) was added. The reaction mixture wasallowed to warm to room temperature overnight. The reaction was quenchedwith a saturated aqueous solution of NH₄Cl and diluted with CH₂Cl₂. Thelayers were separated and the aqueous phase was extracted with CH₂Cl₂(2×). Organics combined, dried over Na₂SO₄, filtered, and concentratedto afford a yellow residue. The crude material was dissolved in aminimal amount of CH₂Cl₂ to be chromatographed. Purification of thecrude material by silica gel chromatography using an ISCO machine (80 gcolumn, 60 mL/min, 0-30% EtOAc in hexanes over 20 min, t_(r)=17.5 min)gave the title compound (1.62 g, 4.92 mmol, 100% yield) as a colorlessliquid.

Preparation 35B:(3-Bromo-2-fluorophenyl)(5-fluoro-2-methoxyphenyl)methanone

To a solution of Preparation 35A (1.62 g, 4.92 mmol) in wet CH₂Cl₂(19.69 mL) was added Dess-Martin periodinane (5.22 g, 12.31 mmol) atroom temperature. After 2.5 hr, the reaction was quenched with a 1:1solution of saturated aqueous NaHCO₃:10% (w/w) aqueous Na₂S₂O₃. Thereaction mixture was diluted with additional CH₂Cl₂. The mixture wasstirred until both layers became clear. The layers were separated andthe organic phase washed with saturated aqueous NaHCO₃. The aqueousphase was extracted with CH₂Cl₂ (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford the titlecompound (1.61 g, 4.92 mmol, 100% yield) as an off-white solid.

Preparation 35C:(Z)-(3-Bromo-2-fluorophenyl)(5-fluoro-2-methoxyphenyl)methanone oxime

A solution of Preparation 35B (1.46 g, 4.46 mmol) and hydroxylaminehydrochloride (2.109 g, 30.3 mmol) in pyridine (Volume: 22.32 ml) wasrefluxed for 1.5 hr, allowed to cool to room temperature, thenconcentrated in vacuo. The crude material was partitioned between EtOAcand 1N HCl. The layers were separated and the aqueous phase extractedwith EtOAc (3×). Organics combined, dried over Na₂SO₄, filtered, andconcentrated to afford the title compound (1.10 g, 3.18 mmol, 71.3%yield) as a yellow residue.

Preparation 35D: 7-Bromo-3-(5-fluoro-2-methoxyphenyl)benzo[d]isoxazole

To a suspension of sodium hydride (0.219 g, 5.47 mmol) in THF (Ratio:1.8, Volume: 41.3 ml) was added dropwise Preparation 35C (1.10 g, 3.22mmol) in DMF (11 mL) slowly. The syringe was rinsed with additional DMF(10 mL) into the reaction vial. The reaction mixture was heated at 70°C. for 3 hr, then allowed to cool to room temperature. The reaction wasquenched with H₂O. The reaction mixture was extracted with EtOAc (3×).The organic phases were combined, dried over Na₂SO₄, filtered,concentrated, and further dried under high vacuum to afford a yellowsolid. The crude material was dissolved in a minimal amount of CH₂Cl₂ tobe chromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (80 g column, 60 mL/min, 0-95%EtOAc in hexanes over 30 min, t_(r)=2, 12 min) gave an insoluble whitesolid. Further trituration of the product with CH₂Cl₂ at roomtemperature and filtration through a Buchner funnel provided the titlecompound (765 mg, 2.351 mmol, 73.1% yield).

Example 35

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 35D (0.032 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 4-methylpyridin-3-ylboronic acid (14.38 mg, 0.105 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(Ratio: 2.0, Volume: 373 μl), EtOH (Ratio: 1.0, Volume: 1870, and water(Ratio: 1.000, Volume: 187 μl) were added sequentially. The resultantmixture was heated at 90° C. overnight. After 17.5 hr, the reactionmixture was allowed to cool to room temperature. The reaction wasquenched with water. The reaction mixture was diluted with EtOAc. Thelayers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (13 mg, 37%). ESI MS (M+H)⁺=335.2. HPLC Peakt_(r)=2.58 minutes. Purity=99%. HPLC Conditions: D.

Example 363-(5-Fluoro-2-methoxyphenyl)-7-(4-morpholinopyrimidin-5-yl)benzo[d]isoxazole

Preparation 36A:3-(5-Fluoro-2-methoxyphenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole

A vial was charged with bis(acetonitrile)palladium(II) chloride (4.67mg, 0.018 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(0.015 g, 0.036 mmol), and Preparation 35D (0.290 g, 0.900 mmol). Thevial was capped with a rubber septum and then evacuated and backfilledwith N₂ (this sequence was carried out a total of 2 times). Dioxane(Volume: 0.539 ml) was added via syringe through the septum, followed bythe addition of triethylamine (0.376 ml, 2.70 mmol) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.196 ml, 1.350 mmol). Theseptum was then replaced with a Teflon screw valve, and the vial sealed.The reaction mixture was heated at 110° C. After 13 hr, the reactionmixture was allowed to cool to room temperature. The reaction mixturewas filtered through a disposable fritted funnel and the filter cakewashed with CH₂Cl₂. The filtrate was concentrated to afford the titlecompound (332 mg, 100%) as a yellow-green residue.

Example 36

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 16A (43.7 mg, 0.150 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 36A (0.037 g, 0.100 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.0, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 14 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 10-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (14 mg, 35%). ESI MS (M+H)⁺=407.2. HPLC Peakt_(r)=2.29 minutes. Purity=98%. HPLC Conditions: D.

Example 373-(5-Fluoro-2-methoxyphenyl)-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 36A (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 5-bromo-4-methylpyrimidine (26.0 mg, 0.150 mmol). The mixturewas stirred at room temperature for 10 min under N₂, then DME (Ratio:2.0, Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water(Ratio: 1.000, Volume: 187 μl) were added sequentially. The resultantmixture was heated at 90° C. overnight. After 14 hr, the reactionmixture was allowed to cool to room temperature. The reaction wasquenched with water. The reaction mixture was diluted with EtOAc. Thelayers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (12.7 mg, 37%). ESI MS (M+H)⁺=336.1. HPLC Peakt_(r)=2.32 minutes. Purity=97%. HPLC Conditions: D.

Example 387-(4-Chloropyridin-3-yl)-3-(5-fluoro-2-methoxyphenyl)benzo[d]isoxazole

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 35D (0.032 g, 0.100 mmol), sodium carbonate (0.042 g, 0.400mmol), and4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.072g, 0.300 mmol). The mixture was stirred at room temperature for 10 minunder N₂, then DME (Ratio: 2.0, Volume: 0.373 ml), EtOH (Ratio: 1.0,Volume: 187 μl), and water (Ratio: 1.000, Volume: 187 μl) were addedsequentially. The resultant mixture was heated at 90° C. overnight.After 17.5 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a brown residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 35-70% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (1.7 mg, 4.7%). ESI MS (M+H)⁺=355.0. HPLC Peakt_(r)=2.76 minutes. Purity=99%. HPLC Conditions: B.

Example 397-(4-Cyclopropylpyrimidin-5-yl)-3-(5-fluoro-2-methoxyphenyl)benzo[d]isoxazole

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 36A (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 11A (29.9 mg, 0.150 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.0, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 14 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-70% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (9.4 mg, 26%). ESIMS (M+H)⁺=362.2. HPLC Peak t_(r)=2.81 minutes. Purity >99%. HPLCConditions: B.

Example 403-(5-Fluoro-2-methoxyphenyl)-7-(4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)benzo[d]isoxazole

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 36A (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 12A (45.6 mg, 0.150 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 14 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 20-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-70% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (9.4 mg, 22%). ESIMS (M+H)⁺=420.2. HPLC Peak t_(r)=2.91 minutes. Purity >99%. HPLCConditions: B.

Example 413-(5-Fluoro-2-methoxyphenyl)-7-(isoquinolin-4-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 35D (0.032 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and isoquinolin-4-ylboronic acid (18.16 mg, 0.105 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(Ratio: 2.0, Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), andwater (Ratio: 1.000, Volume: 187 μl) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 24 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation (12mg, 33%). ESI MS (M+H)⁺=371.1. HPLC Peak t_(r)=2.91 minutes. Purity=99%.HPLC Conditions: B.

Example 425-(3-(5-Fluoro-2-methoxyphenyl)benzo[d]isoxazol-7-yl)pyrimidin-4-amine

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),5-iodopyrimidin-4-amine (33.1 mg, 0.150 mmol), sodium carbonate (42.4mg, 0.400 mmol), and Preparation 36A (0.037 g, 0.100 mmol). The mixturewas stirred at room temperature for 10 min under N₂, then DME (Ratio:2.0, Volume: 373 μl), EtOH (Ratio: 1.0, Volume: 187 μl), and water(Ratio: 1.000, Volume: 187 μl) were added sequentially. The resultantmixture was heated at 90° C. overnight. After 17 hr, the reactionmixture was allowed to cool to room temperature. The reaction wasquenched with water. The reaction mixture was diluted with EtOAc. Thelayers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 10-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (9.3 mg, 27%). ESI MS (M+H)⁺=337.1. HPLC Peakt_(r)=1.52 minutes. Purity >99%. HPLC Conditions: E.

Example 433-(4-Fluoro-2-methoxyphenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

Preparation 43A:(3-Bromo-2-fluorophenyl)(4-fluoro-2-methoxyphenyl)methanol

To a solution of 3-bromo-2-fluorobenzaldehyde (1.5 g, 7.39 mmol) in THF(Volume: 32.1 ml) cooled to 0° C. was added(4-fluoro-2-methoxyphenyl)magnesium bromide (17.73 ml, 8.87 mmol). After50 min, additional (4-fluoro-2-methoxyphenyl)magnesium bromide (17.73ml, 8.87 mmol) was added. The reaction was quenched with a saturatedaqueous solution of NH₄Cl. The reaction mixture was diluted with CH₂Cl₂.The layers were separated and the aqueous phase extracted with CH₂Cl₂(2×). Organics combined, dried over Na₂SO₄, filtered, and concentratedto afford a yellow residue. The crude material was dissolved in aminimal amount of CH₂Cl₂ to be chromatographed. Purification of thecrude material by silica gel chromatography using an ISCO machine (80 gcolumn, 60 mL/min, 0-30% EtOAc in hexanes over 30 min, tr=17 min) gavethe title compound (2.10 g, 6.06 mmol, 82% yield) as a colorless liquid.

Preparation 43B:(3-Bromo-2-fluorophenyl)(4-fluoro-2-methoxyphenyl)methanone

To a solution of Preparation 43A (2.10 g, 6.38 mmol) in wet CH₂Cl₂(Volume: 25.5 ml) was added Dess-Martin periodinane (6.77 g, 15.96 mmol)at room temperature. After 2 hr, the reaction was quenched with a 1:1solution of saturated aqueous NaHCO₃: 10% (w/w) aqueous Na₂S₂O₃. Thereaction mixture was diluted with additional CH₂Cl₂. The mixture wasstirred until both layers became clear. The layers were separated andthe organic phase washed with saturated aqueous NaHCO₃. The aqueousphase was extracted with CH₂Cl₂ (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.Purification of the crude material by silica gel chromatography using anISCO machine (80 g column, 60 mL/min, 0-30% EtOAc in hexanes over 17min, t_(r)=11 min) gave the title compound (1.83 g, 5.54 mmol, 87%yield) as a white solid.

Preparation 43C:(Z)-(3-Bromo-2-fluorophenyl)(4-fluoro-2-methoxyphenyl)methanone oxime

A solution of Preparation 43B (1.83 g, 5.59 mmol) and hydroxylaminehydrochloride (2.64 g, 38.0 mmol) in pyridine (Volume: 28.0 ml) wasrefluxed for 1.5 hr, allowed to cool to room temperature, and thenconcentrated in vacuo. The crude material was partitioned between EtOAcand 1N HCl. The layers were separated and the aqueous phase extractedwith EtOAc (3×). The organics were combined, dried over Na₂SO₄,filtered, and concentrated to afford the title compound (1.914 g, 5.59mmol, 100% yield) as a yellow solid.

Preparation 43D: 7-Bromo-3-(4-fluoro-2-methoxyphenyl)benzo[d]isoxazole

To a suspension of sodium hydride (0.219 g, 5.47 mmol) in THF (Ratio:1.8, Volume: 41.3 ml) was added dropwise Preparation 43C (1.10 g, 3.22mmol) in DMF (13 mL) slowly. The syringe was rinsed with additional DMF(10 mL) into the reaction vial. The reaction mixture was heated at 70°C. for 3 hr and then allowed to cool to room temperature. The reactionwas quenched with H₂O. The reaction mixture was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered,concentrated, and further dried under high vacuum to afford a yellowsolid. The crude material was dissolved in a minimal amount of CH₂Cl₂ tobe chromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (80 g column, 60 mL/min, 0-50%EtOAc in hexanes over 25 min, t_(r)=12 min) gave the title compound (487mg, 1.436 mmol, 44.7% yield) as a white solid.

Example 43

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 43D (0.032 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 4-methylpyridin-3-ylboronic acid (14.38 mg, 0.105 mmol). Themixture was stirred at room temperature for 10 min under N₂, and thenDME (Ratio: 2.0, Volume: 373 μl), EtOH (Ratio: 1.0, Volume: 1870, andwater (Ratio: 1.000, Volume: 187 μl) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 17 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (3.6 mg, 10%).

Example 447-(4-Chloropyridin-3-yl)-3-(4-fluoro-2-methoxyphenyl)benzo[d]isoxazole

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 43D (0.032 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (71.9mg, 0.300 mmol). The mixture was stirred at room temperature for 10 minunder N₂, then DME (Ratio: 2.0, Volume: 373 μl), EtOH (Ratio: 1.0,Volume: 187 μl), and water (Ratio: 1.000, Volume: 187 μl) were addedsequentially. The resultant mixture was heated at 90° C. overnight.After 17 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a brown residue. Thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 35-70% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (1.7 mg, 4.7%). ESI MS (M+H)⁺=355.0. HPLC Peakt_(r)=2.77 minutes. Purity >99%. HPLC Conditions: B.

Example 453-(4-Fluoro-2-methoxyphenyl)-7-(4-morpholinopyrimidin-5-yl)benzo[d]isoxazole

Preparation 45A:3-(4-Fluoro-2-methoxyphenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole

A vial was charged with bis(acetonitrile)palladium(II) chloride (3.87mg, 0.015 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(0.012 g, 0.030 mmol), and Preparation 43D (0.240 g, 0.745 mmol). Thevial was capped with a rubber septum and then evacuated and backfilledwith N₂ (this sequence was carried out a total of 2 times). Dioxane(Volume: 0.446 ml) was added via syringe, through the septum, followedby the addition of triethylamine (0.312 ml, 2.235 mmol) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.162 ml, 1.118 mmol). Theseptum was then replaced with a Teflon screw valve, and the vial sealed.The reaction mixture was heated at 110° C. After 13.5 hr, the reactionmixture was allowed to cool to room temperature. The reaction mixturewas filtered through a disposable fritted funnel and the filter cakewashed with CH₂Cl₂. The filtrate was concentrated to afford the titlecompound (275 mg, 100%) as a yellow residue.

Example 45

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 16A (37.8 mg, 0.130 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 45A (0.037 g, 0.100 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and Water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 14 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (12 mg, 30%). ESI MS (M+H)⁺=407.2. HPLC Peakt_(r)=2.34 minutes. Purity >99%. HPLC Conditions: B.

Example 463-(4-Fluoro-2-methoxyphenyl)-7-(4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)benzo[d]isoxazole

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 45A (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 12A (39.5 mg, 0.130 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.0, Volume: 187 μl), and Water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 14 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (14 mg, 32%). ESI MS (M+H)⁺=420.1. HPLC Peakt_(r)=2.92 minutes. Purity=97%. HPLC Conditions: B.

Example 473-(4-Fluoro-2-methoxyphenyl)-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (57.8 mg, 0.050 mmol),Preparation 45A (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 5-bromo-4-methylpyrimidine (39.8 mg, 0.230 mmol). The mixturewas stirred at room temperature for 10 min under N₂, then DME (Ratio:2.0, Volume: 373 μl), EtOH (Ratio: 1.0, Volume: 187 μl), and water(Ratio: 1.000, Volume: 187 μl) were added sequentially. The resultantmixture was heated at 90° C. overnight. After 14 hr, the reactionmixture was allowed to cool to room temperature. The reaction wasquenched with water. The reaction mixture was diluted with EtOAc. Thelayers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (6.0 mg, 18%). ESI MS (M+H)⁺=336.1. HPLC Peakt_(r)=2.37 minutes. Purity >99%. HPLC Conditions: B.

Example 487-(4-Cyclopropylpyrimidin-5-yl)-3-(4-fluoro-2-methoxyphenyl)benzo[d]isoxazole

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 45A (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 11A (25.9 mg, 0.130 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.0, Volume: 187 μl), and water (Ratio:1.0, Volume: 187 μl) were added sequentially. The resultant mixture washeated at 90° C. overnight. After 14 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (10 mg, 28%). ESI MS (M+H)⁺=362.2. HPLC Peakt_(r)=2.13 minutes. Purity=99%. HPLC Conditions: E.

Example 493-(4-Fluoro-2-methoxyphenyl)-7-(isoquinolin-4-yl)benzo[d]isoxazole

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 43D (0.032 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and isoquinolin-4-ylboronic acid (18.16 mg, 0.105 mmol). Themixture was stirred at room temperature for 10 min under N₂, then DME(Ratio: 2.0, Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), andwater (Ratio: 1.000, Volume: 187 μl) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 24 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (7.9 mg, 21%). ESI MS (M+H)⁺=371.1. HPLC Peakt_(r)=2.21 minutes. Purity >99%. HPLC Conditions: E.

Example 50 3-Chloro-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

Preparation 50A: 2-Fluoro-3-(4-methylpyridin-3-yl)benzonitrile

A reaction flask was charged withtetrakis(triphenylphosphine)palladium(0) (1.040 g, 0.900 mmol),3-bromo-2-fluorobenzonitrile (3.6 g, 18.00 mmol), sodium carbonate (7.63g, 72.0 mmol), and 4-methylpyridin-3-ylboronic acid (2.59 g, 18.90mmol). The mixture was stirred at room temperature for 10 min under N₂,then DME (67.2 mL), EtOH (33.6 mL), and water (33.6 mL) were addedsequentially. The resultant mixture was heated at 90° C. overnight.After 17 hr, the reaction mixture was allowed to cool to roomtemperature. The reaction was quenched with water. The reaction mixturewas diluted with EtOAc. The layers were separated and the aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a brown residue. Thecrude material was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (120 g column, 85 mL/min, 0-70%EtOAc in hexanes over 25 min, t_(r)=15 min) gave the title compound(2.80 g, 13.19 mmol, 73.3% yield) as a purple residue. ESI MS(M+H)⁺=213.1. HPLC Peak t_(r)=1.01 minutes. Purity >99%. HPLCConditions: C.

Preparation 50B: 7-(4-Methylpyridin-3-yl)benzo[d]isoxazol-3-amine

A mixture of Preparation 50A (2.80 g, 13.19 mmol), N-hydroxyacetamide(2.97 g, 39.6 mmol), and potassium carbonate (10.94 g, 79 mmol) in DMF(57.7 mL) and Water (8.25 mL) was heated at 80° C. for 3 hr. Thereaction mixture was filtered through a fritted funnel and the filtercake was washed with EtOAc. The layers in the filtrate were separated.The aqueous phase was extracted with EtOAc (3×). The organic phases werecombined, washed with water (2×), brine (2×), dried over Na₂SO₄,filtered, concentrated, and further dried under high vacuum to afford abrown residue. The crude material was dissolved in a minimal amount ofCH₂Cl₂ to be chromatographed. Purification of the crude material bysilica gel chromatography using an ISCO machine (120 g column, 85mL/min, 0-100% EtOAc in hexanes over 40 min, t_(r)=32 min) gave thetitle compound (2.07 g, 9.19 mmol, 69.7% yield) as a white solid. ESI MS(M+H)⁺=226.1. HPLC Peak t_(r)=0.82 minutes. Purity=96%. HPLC Conditions:C.

Example 50 3-Chloro-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

To a solution of Preparation 50B (1.1 g, 4.88 mmol) in concentratedhydrochloric Acid, 37% (50.9 mL) cooled to 0° C. was added sodiumnitrite (0.354 g, 5.13 mmol). The reaction mixture was stirred at 0° C.for 1 hr and then allowed to stir at room temperature for 2 hr. Themixture was poured into a solution of saturated aqueous NH₄Cl (50 mL). Ayellow solid precipitated. The suspension was allowed to stir at roomtemperature overnight, then neutralized with solid NaHCO₃ (52 g+5 g) anddiluted with CH₂Cl₂. The layers were separated, and the aqueous phasewas extracted with CH₂Cl₂ (5×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford a yellow residue. Thecrude material was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (80 g column, 60 mL/min, 50-70%EtOAc in hexanes over 25 min, t_(r)=12 min) gave the title compound(1.08 g, 4.41 mmol, 90% yield) as a white solid. ESI MS (M+H)⁺=245.1.HPLC Peak t_(r)=1.47 minutes. Purity >99%. HPLC Conditions: C.

Example 517-(4-(1H-Pyrazol-1-yl)pyrimidin-5-yl)-3-(2-chlorophenyl)benzo[d]isoxazole

Preparation 51A: (3-Bromo-2-fluorophenyl)(2-chlorophenyl)methanol

To a stirring solution of 1-chloro-2-iodobenzene (7.05 g, 29.6 mmol) intetrahydrofuran (Volume: 15 mL) at −15° C. was added isopropylmagnesiumchloride (17.24 mL, 34.5 mmol). The mixture was allowed to stir for 30minutes, at which time 3-bromo-2-fluorobenzaldehyde (5 g, 24.63 mmol)was added. The reaction mixture was stirred overnight. The reaction wasquenched with saturated aqueous NH₄Cl. The reaction mixture wasextracted with EtOAc (3×). The organics were combined, rinsed withbrine, dried over Na₂SO₄, filtered, and concentrated to afford the titlecompound (7.5 g, 96%).

Preparation 51B: (3-Bromo-2-fluorophenyl)(2-chlorophenyl)methanone

To a stirring solution of Preparation 51A (7.5 g, 23.77 mmol) in DCM(Volume: 300 mL) at room temperature was added Dess-Martin Periodinane(11.09 g, 26.1 mmol). The mixture was allowed to stir until judgedcomplete by HPLC. The reaction was quenched by addition of 10% Na₂S₂O₃with stirring followed by addition of saturated aqueous NaHCO₃. Thesolution was extracted DCM (2×). The combined organics were dried overNa₂SO₄, filtered, and concentrated to afford the title compound (7.5 g,100%).

Preparation 51C: (E)-(3-Bromo-2-fluorophenyl)(2-chlorophenyl)methanoneoxime

A solution of Preparation 51B (7.21 g, 23 mmol) and hydroxylaminehydrochloride (10.87 g, 156 mmol) in pyridine (Volume: 115 ml) wasrefluxed for 40 min, allowed to cool to room temperature, and thenconcentrated in vacuo. The crude material was partitioned between EtOAcand 1N HCl. The layers were separated and the aqueous phase extractedwith EtOAc (3×). Organics combined, dried over Na₂SO₄, filtered, andconcentrated to afford the title compound (7.56 g, 23.00 mmol, 100%yield) as a yellow residue.

Preparation 51D: 7-Bromo-3-(2-chlorophenyl)benzo[d]isoxazole

To a suspension of sodium hydride (1.564 g, 39.1 mmol) in THF (Ratio:1.8, Volume: 148 ml) was added dropwise Preparation 51C (7.56 g, 23mmol) in DMF (4 mL). The syringe was rinsed with additional DMF (3.7 mL)into the reaction vial. The reaction mixture was heated at roomtemperature for 3 hr and then allowed to cool to room temperature.Additional NaH (102 mg, 2.55 mmol) was added. The reaction was quenchedwith H₂O. The reaction mixture was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, concentrated,and further dried under high vacuum to afford a yellow solid. The crudematerial was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (80 g column, 60 mL/min, 0-40%EtOAc in hexanes over 20 min, t_(r)=13 min) gave the title compound (3.0g, 9.72 mmol, 42.3% yield) as a white solid.

Preparation 51E:3-(2-Chlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole

A vial was charged with bis(acetonitrile)palladium(II) chloride (7.78mg, 0.030 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(0.025 g, 0.060 mmol), and Preparation 51D (0.463 g, 1.5 mmol). The vialwas capped with a rubber septum and then evacuated and backfilled withN₂ (this sequence was carried out a total of 2 times). Dioxane (Volume:0.898 ml) was added via syringe, through the septum, followed by theaddition of triethylamine (0.627 ml, 4.50 mmol) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.326 ml, 2.250 mmol). Theseptum was then replaced with a Teflon screw valve, and the vial sealed.The reaction mixture was heated at 110° C. After 17 hr, the reactionmixture was allowed to cool to room temperature. The reaction mixturewas filtered through a disposable fritted funnel and the filter cakewashed with CH₂Cl₂. The filtrate was concentrated to afford the titlecompound (533 mg, 100%) as a yellow solid.

Example 51

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 51E (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and 5-iodo-4-(1H-pyrazol-1-yl)pyrimidine (40.8 mg, 0.150 mmol).The mixture was stirred at room temperature for 10 min under N₂, thenDME (Ratio: 2.0, Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl),and water (Ratio: 1.000, Volume: 187 μl) were added sequentially. Theresultant mixture was heated at 90° C. overnight. After 14 hr, thereaction mixture was allowed to cool to room temperature. The reactionwas quenched with water. The reaction mixture was diluted with EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc(3×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient: 25-85% B over 25 minutes,then a 10-minute hold at 100% B; Flow: 20 mL/min. Fractions containingthe desired product were combined and dried via centrifugal evaporationto afford the title compound (4.0 mg, 10%). ESI MS (M+H)⁺=374.0. HPLCPeak t_(r)=2.63 minutes. Purity=97%. HPLC Conditions: C.

Example 527-(4-(1H-1,2,4-Triazol-1-yl)pyrimidin-5-yl)-3-(2-chlorophenyl)benzo[d]isoxazole

Preparation 52A: 5-Iodo-4-(1H-1,2,4-triazol-1-yl)pyrimidine

To a solution of 1H-1,2,4-triazole (0.158 g, 2.288 mmol) in THF (Volume:6.03 ml) cooled to 0° C. was added NaH (0.100 g, 2.496 mmol). Thereaction mixture was stirred for 30 min at this temperature and then4-chloro-5-iodopyrimidine (0.500 g, 2.080 mmol) was added. The reactionmixture was allowed to warm to room temperature. After 16 hr, reactionquenched with saturated aqueous NH₄Cl and diluted with EtOAc. Theaqueous and organic layers were separated. Aqueous phase was extractedwith EtOAc (3×). The organics layers were combined, dried over Na₂SO₄,filtered, and concentrated to afford an orange residue. The crudematerial was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (40 g column, 40 mL/min, 20-80%EtOAc in hexanes over 20 min, t_(r)=13 min) gave5-iodo-4-(1H-pyrazol-1-yl)pyrimidine (113 mg, 20%) as a white solid.

Example 52

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 51E (0.036 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 52A (41.0 mg, 0.150 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 14 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% Bover 25 minutes, then a 15-minute hold at 60% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (3.4 mg, 9.0%). ESIMS (M+H)⁺=375.1. HPLC Peak t_(r)=2.22 minutes. Purity >99%. HPLCConditions: C.

Example 53(R)-1-(5-(3-(2-Chlorophenyl)benzo[d]isoxazol-7-yl)pyrimidin-4-yl)-3-methylpyrrolidin-3-ol

Preparation 53A: (R)-1-(5-Iodopyrimidin-4-yl)-3-methylpyrrolidin-3-ol

To a solution of (R)-3-methylpyrrolidin-3-ol, HCl (0.126 g, 0.915 mmol)in THF (Volume: 2.411 ml) cooled to 0° C. was added NaH (0.080 g, 1.996mmol). The reaction mixture was stirred for 30 min, then4-chloro-5-iodopyrimidine (0.200 g, 0.832 mmol) was added. After 16 hr,the reaction was quenched with a saturated aqueous NH₄Cl. The reactionmixture was diluted with EtOAc. The aqueous and organic layers wereseparated. The aqueous phase was extracted with EtOAc (3×). The organicslayers were combined, dried over Na₂SO₄, filtered, and concentrated toafford an orange residue. The crude material was dissolved in a minimalamount of CH₂Cl₂ to be chromatographed. Purification of the crudematerial by silica gel chromatography using an ISCO machine (24 gcolumn, 35 mL/min, 40-95% EtOAc in hexanes over 25 min, t_(r)=17 min)gave the title compound (214 mg, 83%) as a yellow residue, whichcrystallized to a yellow solid upon standing.

Example 53

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 51E (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 53A (45.8 mg, 0.150 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 14 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% Bover 25 minutes, then a 15-minute hold at 55% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (8.6 mg, 20%). ESIMS (M+H)⁺=407.1. HPLC Peak t_(r)=2.11 minutes. Purity=93%. HPLCConditions: C.

Example 545-(3-(2-Chlorophenyl)benzo[d]isoxazol-7-yl)-N-cyclopropylpyrimidin-4-amine

Preparation 54A: N-Cyclopropyl-5-iodopyrimidin-4-amine

To a vial containing a solution of 4-chloro-5-iodopyrimidine (0.400 g,1.664 mmol) in DMF (Volume: 2.67 ml) was added cyclopropanamine (0.461ml, 6.65 mmol) followed by cesium carbonate (1.084 g, 3.33 mmol). Thevial was sealed with a Teflon cap and heated at 90° C. for 3 hr, thenallowed to cool to room temperature. The reaction mixture was filteredthrough a disposable fritted funnel and the filter cake washed withEtOAc. The filtrate was diluted with H₂O and the layers were separated.The organic phase was washed with H₂O (2×). The combined aqueous phaseswere back-extracted with EtOAc (3×). All organics were combined, driedover Na₂SO₄, filtered, and concentrated to afford an orange residue. Thecrude material was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (40 g column, 40 mL/min, 20-70%EtOAc in hexanes over 19 min, t_(r)=13.5 min) gave the title compound(348 mg, 1.320 mmol, 79% yield) as a yellow solid. ESI MS (M+H)⁺=262.0.

Example 54

A reaction vial was charged withtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol),Preparation 51E (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400mmol), and Preparation 54A (39.2 mg, 0.150 mmol). The mixture wasstirred at room temperature for 10 min under N₂, then DME (Ratio: 2.0,Volume: 373 μl), EtOH (Ratio: 1.000, Volume: 187 μl), and water (Ratio:1.000, Volume: 187 μl) were added sequentially. The resultant mixturewas heated at 90° C. overnight. After 14 hr, the reaction mixture wasallowed to cool to room temperature. The reaction was quenched withwater. The reaction mixture was diluted with EtOAc. The layers wereseparated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (14 mg, 38%). ESI MS (M+H)⁺=363.1. HPLC Peakt_(r)=2.35 minutes. Purity=98%. HPLC Conditions: C.

Example 553-(2-Chlorophenyl)-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole

To a pressure tube were added Preparation 51E (35.6 mg, 0.100 mmol),5-bromo-4-methylpyrimidine (26.0 mg, 0.150 mmol), and sodium carbonate(53.0 mg, 0.500 mmol) in water (Ratio: 1.000, Volume: 0.750 mL), DME(Ratio: 2, Volume: 1.5 mL) and EtOH (Ratio: 1.000, Volume: 0.750 mL) atroom temperature. To this slurry was addedtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol) and thesystem was purged with nitrogen and sealed. The vessel was heated to 90°C. for 12 h and then allowed to cool to room temperature. The reactionmixture was diluted with MeOH, filtered, and concentrated. The remainingoil was diluted with DMF and purified via preparative LC/MS with thefollowing conditions: Column: Waters XBridge C18, 19×250 mm, 5-μmparticles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation. The material was further purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 20-60% B over 25 minutes, then a15-minute hold at 60% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the title compound (1.7 mg, 4.9%). ESI MS (M+H)⁺=322.1. HPLC Peakt_(r)=2.44 minutes. Purity=92%. HPLC Conditions: C. ¹H NMR (500 MHz,MeOD) δ ppm 9.11 (1 hr, s), 8.74 (1 hr, s), 7.78 (1 hr, dd, J=7.91, 1.25Hz), 7.59-7.66 (2 hr, m), 7.46-7.55 (1 hr, m), 2.55 (2 hr, s).

Example 563-(2-Chlorophenyl)-7-(4-ethoxypyrimidin-5-yl)benzo[d]isoxazole

To a pressure tube were added Preparation 51E (35.6 mg, 0.100 mmol),4-ethoxy-5-iodopyrimidine (37.5 mg, 0.150 mmol), and sodium carbonate(53.0 mg, 0.500 mmol) in DME (Ratio: 2, Volume: 1.5 mL), water (Ratio:1.000, Volume: 0.750 mL) and EtOH (Ratio: 1.000, Volume: 0.750 mL) atroom temperature. To this slurry was addedtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol) and thesystem was purged with nitrogen and sealed. The vessel was heated to 90°C. for 12 hr, then allowed to cool to room temperature. The reactionmixture was diluted with MeOH, filtered and concentrated. The remainingoil was diluted with DMF and the crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-60% Bover 25 minutes, then a 15-minute hold at 60% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (1.8 mg, 4.9%). ESIMS (M+H)⁺=352.1. HPLC Peak t_(r)=2.89 minutes. Purity=95%. HPLCConditions: C. ¹H NMR (500 MHz, MeOD) δ ppm 8.77 (1 hr, s), 8.75 (1 hr,s), 7.79-7.82 (1 hr, m), 7.70 (1 hr, dd, J=8.05, 1.11 Hz), 7.62 (1 hr,td, J=7.91, 1.39 Hz), 7.52-7.55 (1 hr, m), 7.48 (1 hr, t, J=7.77 Hz),4.53-4.59 (3 hr, m), 1.38 (2 hr, t, J=7.07 Hz).

Example 577-(4-(2H-1,2,3-Triazol-2-yl)pyrimidin-5-yl)-3-(2-chlorophenyl)benzo[d]isoxazole

Preparation 57A: 5-Iodo-4-(2H-1,2,3-triazol-2-yl)pyrimidine

To a solution of 1H-1,2,3-triazole (63.2 mg, 0.915 mmol) in THF (Volume:2411 μl), was added portion wise at 0° C., NaH (39.9 mg, 0.998 mmol).The reaction mixture was stirred at that temperature for 30 min, then4-chloro-5-iodopyrimidine (200 mg, 0.832 mmol) was added. The reactionmixture was allowed to warm to room temperature. To this solution wasadded saturated aqueous NH₄Cl and the mixture was allowed to stir for 5min at which time it was diluted with ethyl acetate and extracted 2×.The combined organics were washed with brine 1×. The organics were driedover Na₂SO₄, filtered and concentrated in vacuo to afford the titlecompound (90 mg, 40%).

Example 57

To a pressure tube were added Preparation 51E (35.6 mg, 0.100 mmol),Preparation 57A (41.0 mg, 0.150 mmol), and sodium carbonate (53.0 mg,0.500 mmol) in DME (Ratio: 2, Volume: 1.5 mL), water (Ratio: 1.000,Volume: 0.750 mL) and EtOH (Ratio: 1.000, Volume: 0.750 mL) at roomtemperature. To this slurry was addedtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol) and thesystem was purged with nitrogen and sealed. The vessel was heated to 90°C. for 12 hr, and then allowed to cool to room temperature. The reactionmixture was diluted with MeOH, filtered, and concentrated. The remainingoil was diluted with DMF and the crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm provided to SCP for purification. particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 25-60% B over 25 minutes, then a 15-minutehold at 60% B; Flow: 20 mL/min. Fractions containing the desired productwere combined and dried via centrifugal evaporation to afford the titlecompound (4.1 mg, 11%). ESI MS (M+H)⁺=375.0. HPLC Peak t_(r)=2.31minutes. Purity=91%. HPLC Conditions: C.

Example 58 3-(2-Chlorophenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

A pressure vessel was charged with Preparation 51D (31 mg, 0.100 mmol),4-methylpyridin-3-ylboronic acid (16.51 mg, 0.121 mmol), and sodiumcarbonate (53.2 mg, 0.502 mmol). To the vessel was then added DME(Ratio: 2, Volume: 1.5 mL), EtOH (Ratio: 1.000, Volume: 0.750 mL), andwater (Ratio: 1.000, Volume: 0.750 mL) at room temperature. To thisslurry was added tetrakis(triphenylphosphine)palladium(0) (58.0 mg,0.050 mmol) and the system was purged with nitrogen and sealed. Thevessel was heated to 90° C. for 12 hr. The reaction mixture was dilutedwith MeOH, filtered, and concentrated. The remaining oil was dilutedwith DMF and the crude material was purified via preparative LC/MS withthe following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μmparticles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation. The material was further purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient: 5-100% B over 25 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to afford the title compound (1.4mg, 4%). ESI MS (M+H)⁺=321.0. HPLC Peak t_(r)=2.71 minutes. Purity=99%.HPLC Conditions: B. ¹H NMR (500 MHz, MeOD) δ ppm 8.56 (2 hr, br. s.),7.74-7.80 (1 hr, m), 7.68-7.73 (1 hr, m), 7.65-7.68 (2 hr, m), 7.62 (1hr, td, J=7.77, 1.94 Hz), 7.52-7.59 (3 hr, m), 2.36 (3 hr, s).

Example 59 3-(2-Chlorophenyl)-7-(isoquinolin-4-yl)benzo[d]isoxazole

A pressure vessel was charged with Preparation 51D (31 mg, 0.100 mmol),isoquinolin-4-ylboronic acid (20.85 mg, 0.121 mmol), and sodiumcarbonate (53.2 mg, 0.502 mmol). To the vessel was then added DME(Ratio: 2, Volume: 1.5 mL), EtOH (Ratio: 1.000, Volume: 0.750 mL), andwater (Ratio: 1.000, Volume: 0.750 mL) at room temperature. To thisslurry was added tetrakis(triphenylphosphine)palladium(0) (58.0 mg,0.050 mmol) and the system was purged with nitrogen and sealed. Thevessel was heated to 90° C. for 12 hr. The reaction mixture was dilutedwith MeOH, filtered, and concentrated. The remaining oil was dilutedwith DMF and the crude material was purified via preparative LC/MS withthe following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μmparticles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B:95:5 acetonitrile:water with 0.05% TFA; Gradient: 15-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: Waters XBridge C18, 19×250 mm,5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 25-70%B over 25 minutes, then a 15-minute hold at 70% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05%TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient:20-60% B over 25 minutes, then a 15-minute hold at 60% B; Flow: 20mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation to afford the title compound (2.3 mg, 5.5%).ESI MS (M+H)⁺=357.0. HPLC Peak t_(r)=2.98 minutes. Purity=86%. HPLCConditions: B. ¹H NMR (500 MHz, MeOD) δ ppm 9.48 (1 hr, s), 8.64 (1 hr,s), 8.34 (1 hr, d, J=7.49 Hz), 7.82-7.91 (4 hr, m), 7.78 (1 hr, d,J=8.32 Hz), 7.71 (2 hr, ddd, J=11.65, 7.77, 1.39 Hz), 7.61-7.67 (2 hr,m), 7.54-7.60 (1 hr, m).

Example 607-(4-(1H-Imidazol-1-yl)pyrimidin-5-yl)-3-(2-chlorophenyl)benzo[d]isoxazole

Preparation 60A: 4-(1H-Imidazol-1-yl)-5-iodopyrimidine

To a solution of 1H-imidazole (0.085 g, 1.248 mmol) in THF (Volume: 10mL) was added sodium hydride (0.062 g, 1.560 mmol). After 15 minutes atroom temperature, 4-chloro-5-iodopyrimidine (0.25 g, 1.040 mmol) wasadded as a solution in THF (5 mL). After 2 h at room temperature, thereaction was quenched with water. The reaction mixture was extractedwith EtOAc (3×). The combined organics were dried over MgSO₄, filteredand concentrated to give the title compound (0.155 g, 0.541 mmol, 52.1%yield) as a pale yellow solid. ESI MS (M+H)⁺=273.0.

Example 60

To a solution of Preparation 60A (40.8 mg, 0.150 mmol) and Preparation51E (35.6 mg, 0.1 mmol) in a mixture of DME (1 mL), ethanol (0.5 mL) andwater (0.5 mL) was added Na₂CO₃ (42.4 mg, 0.400 mmol). This suspensionwas degassed with a stream of N₂ for 10 minutes and thentetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol) was addedfollowed by degassing for 10 minutes. The tube was then sealed andheated at 90° C. for 6 hours. The reaction mixture was cooled to roomtemperature and diluted with MeOH. The mixture was then filtered andconcentrated to a brown oil. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (5.0 mg, 13%). ESI MS (M+H)⁺=374.0. HPLC Peakt_(r)=2.15 minutes. Purity=97%. HPLC Conditions: B.

Example 617-(Isoquinolin-4-yl)-3-(2,2,2-trifluoroethoxy)benzo[d]isoxazole

Preparation 61A: 2-Fluoro-3-(4-methylpyridin-3-yl)benzonitrile

To a solution of 3-bromo-2-fluorobenzonitrile (2.0 g, 10.00 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (2.81 g,11.00 mmol) in a mixture of DME (30 mL), ethanol (15 mL), and water (15mL) was added Na₂CO₃ (4.24 g, 40.0 mmol). This suspension was degassedwith a stream of N₂ for 10 minutes and thentetrakis(triphenylphosphine)palladium(0) (0.578 g, 0.500 mmol) was addedfollowed by degassing with nitrogen for 10 minutes. The tube was thensealed and heated to 90° C. for 14 hours. The vessel was cooled to roomtemperature and diluted with EtOAc and water. The mixture was furtherdiluted with brine and extracted three times with EtOAc. The combinedorganics were dried over MgSO₄, filtered, and concentrated to give thecrude product as a brown oil. The crude material was purified by flashchromatography on silica using an ISCO machine (80 g SiO₂ column, 60mL/min, 0-20% acetone in CH₂Cl₂ over 20 minutes, t_(r)=8 minutes) togive the title compound (2.18 g, 8.69 mmol, 87% yield) as a pale yellowsolid. ESI MS (M+H)⁺=249.1.

Preparation 61B: 7-(Isoquinolin-4-yl)benzo[d]isoxazol-3-amine

To a solution of Preparation 61A (1.5 g, 6.04 mmol) in a mixture of DMF(Ratio: 6.00, Volume: 18 mL) and water (Ratio: 1.000, Volume: 3.00 mL)was added potassium carbonate (5.01 g, 36.3 mmol) followed byN-hydroxyacetamide (1.361 g, 18.13 mmol). The mixture was heated at 80°C. for 3 h and then cooled to room temperature. The mixture was dilutedwith EtOAc and washed twice with water, once with brine, and theorganics were dried over MgSO₄. Filtration and concentration gave thecrude product. The crude material was purified by flash chromatographyon silica using an ISCO machine (40 g column, 60 mL/min, 0-15% acetonein CH₂Cl₂ over 15 minutes, t_(r)=13 minutes) to give the title compound(1.39 g, 5.27 mmol, 87% yield) as a white solid. ESI MS (M+H)⁺=262.1.

Preparation 61C: 3-Chloro-7-(isoquinolin-4-yl)benzo[d]isoxazole

To a solution of Preparation 61B (0.5 g, 1.914 mmol) in 12N hydrogenchloride (10 mL, 120 mmol) at 0° C. was added sodium nitrite (0.158 g,2.296 mmol). After 30 minutes at 0° C., the mixture was warmed to roomtemperature and 3 mL of saturated aqueous NH₄Cl was added. The mixturestirred at room temperature overnight. Water was then added and thereaction mixture was neutralized by the addition of a slight excess ofsolid NaHCO₃. The mixture was extracted thrice with CH₂Cl₂ and theorganics were combined and dried over Na₂SO₄. Filtration andconcentration gave the title compound (0.4 g, 1.354 mmol, 70.7% yield)as a white solid. ESI MS (M+H, M+2)⁺=281, 283.

Example 61

To a stirring solution of 2,2,2-trifluoroethanol (19.96 mg, 0.199 mmol)in DMF (1 mL) at room temperature was added Preparation 61C (28 mg,0.100 mmol). The reaction mixture was heated to 60° C. for 3 hr, thendiluted with MeOH, filtered, and concentrated. The residue was dilutedwith DMF and the crude material was purified via preparative LC/MS withthe following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μmparticles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to afford the title compound (5.8mg, 16%). ESI MS (M+H)⁺=345.1. HPLC Peak t_(r)=2.83 minutes. Purity=95%.HPLC Conditions: B. ¹H NMR (500 MHz, MeOD) δ ppm 9.28 (1 hr, s), 8.50 (1hr, s), 8.10-8.20 (1 hr, m), 7.83-7.91 (1 hr, m), 7.71-7.77 (3 hr, m),7.64-7.69 (1 hr, m), 7.49-7.56 (2 hr, m), 4.89 (2 hr, q, J=8.05 Hz).

Example 627-(4-Methylpyridin-3-yl)-3-(2,2,2-trifluoroethoxy)benzo[d]isoxazole

To a stirring solution of 2,2,2-trifluoroethanol (16.35 mg, 0.163 mmol)in DMF (Volume: 1 mL) at room temperature was added sodium hydride (3.92mg, 0.163 mmol). After 3 minutes, Example 50 (20 mg, 0.082 mmol) wasadded. After 1 h, additional sodium hydride was added. The mixture wassubsequently quenched by the addition of 3 drops of water. The resultingsuspension was filtered and rinsed with MeOH, filtered and concentrated.The residue was diluted with DMF and the crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mMammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (13.6 mg, 54%). ESI MS (M+H)⁺=309.0. HPLC Peakt_(r)=2.51 minutes. Purity=100%. HPLC Conditions: B. ¹H NMR (400 MHz,MeOD) δ ppm 8.44 (1 hr, d, J=5.27 Hz), 8.42 (1 hr, s), 7.79 (1 hr, dd,J=7.78, 1.25 Hz), 7.51-7.55 (1 hr, m), 7.47 (1 hr, t, J=7.53 Hz), 7.37(1 hr, d, J=5.27 Hz), 4.88 (3 hr, q, J=8.03 Hz), 2.27 (4 hr, s).

Example 63 3-Isopropoxy-7-(isoquinolin-4-yl)benzo[d]isoxazole

To a stirring solution of propan-2-ol (7.71 mg, 0.128 mmol) in DMF(Volume: 1 mL) at room temperature was added sodium hydride (3.08 mg,0.128 mmol). After 3 minutes, Preparation 61C (18 mg, 0.064 mmol) wasadded. The mixture was allowed to stir until judged complete by HPLC.The reaction mixture was diluted with MeOH, filtered, and concentrated.The residue was diluted with DMF and the crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (3.3 mg, 17%). ESI MS (M+H)⁺=305.1. HPLC Peakt_(r)=2.84 minutes. Purity=100%. HPLC Conditions: B. ¹H NMR (500 MHz,MeOD) δ ppm 9.27 (1 hr, s), 8.50 (1 hr, s), 8.11-8.16 (1 hr, m), 7.78 (1hr, dd, J=7.91, 1.25 Hz), 7.67-7.76 (3 hr, m), 7.65 (1 hr, dd, J=7.21,1.11 Hz), 7.44-7.50 (1 hr, m), 5.10 (1 hr, dt, J=12.28, 6.21 Hz), 1.49(6 hr, d, J=6.38 Hz).

Example 64 3-Isobutoxy-7-(isoquinolin-4-yl)benzo[d]isoxazole

To a stirring solution of 2-methylpropan-1-ol (7.92 mg, 0.107 mmol) inDMF (Volume: 1 mL) at room temperature was added sodium hydride (2.56mg, 0.107 mmol). After 3 minutes, Preparation 61C (15 mg, 0.053 mmol)was added. The mixture was allowed to stir until judged complete byHPLC. The reaction mixture was diluted with MeOH, filtered, andconcentrated. The residue was diluted with DMF and the crude materialwas purified via preparative LC/MS with the following conditions:Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column:Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-100% B over25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (8.4 mg, 49%). ESI MS(M+H)⁺=319.0. HPLC Peak t_(r)=3.15 minutes. Purity >99%. HPLCConditions: B. ¹H NMR (500 MHz, MeOD) δ ppm 9.26 (1 hr, s), 8.49 (1 hr,s), 8.10-8.15 (1 hr, m), 7.80 (1 hr, dd, J=8.05, 1.11 Hz), 7.63-7.73 (4hr, m), 7.48 (1 hr, t, J=7.49 Hz), 4.20 (2 hr, d, J=6.38 Hz), 2.16-2.28(1 hr, m), 1.07 (6 hr, d, J=6.94 Hz).

Example 657-(Isoquinolin-4-yl)-3-(2,2,2-trifluoroethylthio)benzo[d]isoxazole

To a stirring solution of 2,2,2-trifluoroethanethiol (12.41 mg, 0.107mmol) in DMF (Volume: 1 mL) at room temperature was added sodium hydride(2.56 mg, 0.107 mmol). After 3 minutes, Preparation 61C (15 mg, 0.053mmol) was added. The mixture was allowed to stir until judged completeby HPLC. The reaction mixture was diluted with MeOH, filtered, andconcentrated. The residue was diluted with DMF and the crude materialwas purified via preparative LC/MS with the following conditions:Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column:Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (8.6 mg, 45%). ESI MS(M+H)⁺=361.0. HPLC Peak t_(r)=2.82 minutes. Purity >99%. HPLCConditions: B. ¹H NMR (500 MHz, MeOD) δ ppm 9.29 (1 hr, s), 8.51 (1 hr,s), 8.12-8.19 (1 hr, m), 7.78-7.82 (1 hr, m), 7.70-7.76 (3 hr, m),7.63-7.67 (1 hr, m), 7.58 (1 hr, d, J=8.05 Hz), 4.06 (2 hr, q, J=9.52Hz).

Example 667-(Isoquinolin-4-yl)-3-(2,2,2-trifluoroethylthio)benzo[d]isoxazole

To a stirring solution of 2-methoxyethanol (8.13 mg, 0.107 mmol) in DMF(Volume: 1 mL) at room temperature was added sodium hydride (2.56 mg,0.107 mmol). After 3 minutes, Preparation 61C (15 mg, 0.053 mmol) wasadded. The mixture was allowed to stir until judged complete by HPLC.The reaction mixture was diluted with MeOH, filtered, and concentrated.The residue was diluted with DMF and the crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mMammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (6.0 mg, 35%). ESI MS (M+H)⁺=321.1. HPLC Peakt_(r)=2.29 minutes. Purity >99%. HPLC Conditions: B. ¹H NMR (500 MHz,MeOD) δ ppm 9.27 (1 hr, s), 8.50 (1 hr, s), 8.12-8.17 (1 hr, m), 7.84 (1hr, dd, J=8.05, 1.11 Hz), 7.69-7.75 (2 hr, m), 7.67 (2 hr, dd, J=7.49,1.11 Hz), 7.46-7.52 (1 hr, m), 4.57-4.63 (2 hr, m), 3.84-3.88 (2 hr, m),3.47 (3 hr, s).

Example 67 3-(2-Methoxyethoxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

To a stirring solution of 2-methoxyethanol (12.44 mg, 0.163 mmol) in DMF(Volume: 1 mL) at room temperature was added sodium hydride (3.92 mg,0.163 mmol). After 3 minutes, Example 50 (20 mg, 0.082 mmol) was added.The mixture was allowed to stir until judged complete by HPLC. Thereaction mixture was diluted with MeOH, filtered, and concentrated. Theresidue was diluted with DMF and the crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 5-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (13.6 mg, 59%). MS (M+H)⁺=285.1. HPLC Peak t_(r)=1.99minutes. Purity >99%. HPLC Conditions: B. ¹H NMR (500 MHz, MeOD) δ ppm8.40-8.45 (2 hr, m), 7.77 (1 hr, dd, J=7.77, 1.11 Hz), 7.46-7.50 (1 hr,m), 7.42 (1 hr, t, J=7.49 Hz), 7.36 (1 hr, d, J=5.27 Hz), 4.58 (2 hr,dd, J=4.02, 2.36 Hz), 3.83-3.88 (2 hr, m), 3.46 (3 hr, s), 2.27 (3 hr,s).

Example 68 3-(2-Methoxyethoxy)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

To a stirring solution of 2-(dimethylamino)ethanol (14.57 mg, 0.163mmol) in DMF (Volume: 1 mL) at room temperature was added sodium hydride(3.92 mg, 0.163 mmol). After 3 minutes, Example 50 (20 mg, 0.082 mmol)was added. The mixture was allowed to stir until judged complete byHPLC. The reaction mixture was diluted with MeOH, filtered, andconcentrated. The residue was diluted with DMF and the crude materialwas purified via preparative LC/MS with the following conditions:Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column:Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 20-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (13.2 mg, 53%). ESI MS(M+H)⁺=298.1. HPLC Peak t_(r)=1.46 minutes. Purity=98%. HPLC Conditions:B. ¹H NMR (500 MHz, MeOD) δ ppm 8.40-8.45 (2 hr, m), 7.77 (1 hr, dd,J=7.77, 1.11 Hz), 7.46-7.50 (1 hr, m), 7.42 (1 hr, t, J=7.49 Hz), 7.36(1 hr, d, J=5.27 Hz), 4.58 (2 hr, dd, J=4.02, 2.36 Hz), 3.83-3.88 (2 hr,m), 3.46 (3 hr, s), 2.27 (3 hr, s).

Example 69 3-Isopropoxy-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

To a stirring solution of propan-2-ol (9.82 mg, 0.163 mmol) in DMF(Volume: 1 mL) at ambient temperature was added sodium hydride (3.92 mg,0.163 mmol). After 3 minutes, Example 50 (20 mg, 0.082 mmol) was added.The mixture was allowed to stir until judged complete by HPLC. Thereaction mixture was diluted with MeOH, filtered, and concentrated. Theresidue was diluted with DMF and the crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mMammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mMammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (4.8 mg, 22%). ESI MS (M+H)⁺=269.1. HPLC Peakt_(r)=2.55 minutes. Purity >99%. HPLC Conditions: B. ¹H NMR (500 MHz,MeOD) δ ppm 8.39-8.46 (2 hr, m), 7.72 (1 hr, dd, J=7.91, 1.25 Hz),7.45-7.49 (1 hr, m), 7.41 (1 hr, d, J=7.49 Hz), 7.35-7.39 (1 hr, m),5.10 (1 hr, dt, J=12.21, 6.10 Hz), 2.28 (3 hr, s), 1.49 (6 hr, d, J=6.10Hz).

Example 707-(4-Methylpyridin-3-yl)-3-(2,2,2-trifluoroethylthio)benzo[d]isoxazole

To a stirring solution of 2,2,2-trifluoroethanethiol (18.98 mg, 0.163mmol) in DMF (Volume: 1 mL) at room temperature was added sodium hydride(3.92 mg, 0.163 mmol). After 3 minutes, Example 50 (20 mg, 0.082 mmol)was added. The mixture was allowed to stir until judged complete byHPLC. The reaction mixture was diluted with MeOH, filtered, andconcentrated. The residue was diluted with DMF and the crude materialwas purified via preparative LC/MS with the following conditions:Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column:Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (8.2 mg, 31%). ESI MS(M+H)⁺=325.0. HPLC Peak t_(r)=2.57 minutes. Purity >99%. HPLCConditions: B. ¹H NMR (500 MHz, MeOD) δ ppm 8.45 (1 hr, d, J=5.27 Hz),8.43 (1 hr, s), 7.73 (1 hr, dd, J=7.91, 1.25 Hz), 7.54 (1 hr, d, J=1.11Hz), 7.47-7.52 (1 hr, m), 7.38 (1 hr, d, J=4.99 Hz), 4.06 (2 hr, q,J=9.71 Hz), 2.27 (3 hr, s).

Example 71 3-Isobutoxy-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

To a stirring solution of 2-methylpropan-1-ol (12.12 mg, 0.163 mmol) inDMF (Volume: 1 mL) at room temperature was added sodium hydride (3.92mg, 0.163 mmol). After 3 minutes, Example 50 (20 mg, 0.082 mmol) wasadded. The reaction mixture was allowed to stir until judged complete byHPLC. The reaction mixture was diluted with MeOH, filtered, andconcentrated. The residue was diluted with DMF and the crude materialwas purified via preparative LC/MS with the following conditions:Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column:Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (5.7 mg, 25%). ESI MS(M+H)⁺=283.1. HPLC Peak t_(r)=2.88 minutes. Purity >99%. HPLCConditions: B. ¹H NMR (500 MHz, MeOD) δ ppm 8.39-8.47 (2 hr, m), 7.75 (1hr, dd, J=7.91, 1.25 Hz), 7.46-7.49 (1 hr, m), 7.42 (1 hr, t, J=7.49Hz), 7.37 (1 hr, d, J=4.99 Hz), 4.20 (2 hr, d, J=6.38 Hz), 2.28 (3 hr,s), 2.22 (1 hr, dt, J=13.32, 6.66 Hz), 1.07 (6 hr, d, J=6.66 Hz).

Example 72 3-(2-Methoxyphenyl)-7-(4-methylpyridin-3-yl)benzo[d]isoxazole

Preparation 72A: (3-Bromo-2-fluorophenyl)(2-methoxyphenyl)methanol

To a solution of 3-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF(21.42 mL) cooled to −78° C. was added (2-methoxyphenyl)magnesiumbromide in THF (5.91 mL, 5.91 mmol). The reaction mixture was maintainedat −78° C. for at least 1 hr, and then allowed to warm to roomtemperature. The reaction mixture was cooled to 0° C. and additional(2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol) wasadded. The mixture was allowed to warm to room temperature overnight.The reaction was quenched with a saturated aqueous solution of NH₄Cl.The reaction mixture was diluted with DCM. The layers were separated andthe aqueous phase extracted twice with DCM. The organic extracts werecombined, dried over Na₂SO₄, filtered, and concentrated to afford ayellow residue. The crude material was dissolved in a minimal amount ofDCM and purified via silica gel chromatography using an ISCO machine (80g column, 60 mL/min, 0-0% EtOAc in hexanes over 27 min, t_(r)=19 min)gave the title compound (1.22 g, 3.92 mmol, 80% yield) as a pale yellowliquid. ¹H NMR (400 MHz, CD₃OD) δ 7.54-7.40 (m, 2H), 7.35-7.23 (m, 2H),7.09-6.90 (m, 3H), 6.38 (s, 1H), 4.12 (q, J=7.0 Hz, 1H), 3.76 (s, 3H).

Preparation 72B: (3-Bromo-2-fluorophenyl)(2-methoxyphenyl)methanone

To a solution of Preparation 72A (1.22 g, 3.92 mmol) in wet DCM (15.68mL) was added Dess-Martin periodinane (4.16 g, 9.81 mmol) at ambienttemperature. After 2.5 hr, the reaction was quenched with a 1:1 solutionof saturated aqueous NaHCO₃: 10% (w/w) aqueous Na₂S₂O₃. The reactionmixture was diluted with additional DCM. The mixture was stirred untilboth layers became clear. The layers were separated and the organicphase washed with saturated aqueous NaHCO₃. The aqueous phase wasextracted twice with DCM. The organic extracts were combined, dried overNa₂SO₄, filtered, and concentrated to afford the title compound (1.21 g,3.91 mmol, 100% yield) as an orange solid. ESI MS (M, M+2)⁺=309, 311.

Preparation 72C: (Z)-(3-Bromo-2-fluorophenyl)(2-methoxyphenyl)methanoneoxime

A solution of Preparation 72B (1.2 g, 3.88 mmol) and hydroxylaminehydrochloride (1.834 g, 26.4 mmol) in pyridine (19.41 ml) was refluxedfor 40 min, allowed to cool to room temperature, and then concentratedin vacuo. The crude material was partitioned between EtOAc and 1N HCl.The layers were separated and the aqueous phase extracted three timeswith EtOAc. The organic extracts were combined, dried over Na₂SO₄,filtered, and concentrated to afford the title compound (1.258 g, 3.88mmol, 100% yield) as a yellow residue. ESI MS (M, M+2)⁺=324, 326.

Preparation 72D: 7-Bromo-3-(2-methoxyphenyl)benzo[d]isoxazole

To a suspension of sodium hydride (0.264 g, 6.60 mmol) in THF (Ratio:1.8, Volume: 49.9 ml) was added dropwise Preparation 72C (1.258 g, 3.88mmol) in DMF (4 mL). The reaction mixture was heated at 70° C. for 3 hr,and then allowed to cool to room temperature. Additional NaH (102 mg,2.55 mmol) was added. The reaction was quenched with H₂O. The reactionmixture was extracted three times with EtOAc. The organic extracts werecombined, dried over Na₂SO₄, filtered, concentrated, and further driedunder high vacuum to afford a yellow solid. The crude material wasdissolved in a minimal amount of DCM and purified via silica gelchromatography using an ISCO machine (80 g column, 60 mL/min, 0-40%EtOAc in hexanes over 20 min, t_(r)=13 min) gave the title compound (1.0g, 3.29 mmol, 85% yield) as a white solid. ESI MS (M, M+2)⁺=304, 306.

Example 72

To a stirring solution of 4-methylpyridin-3-ylboronic acid (10.81 mg,0.079 mmol) and Preparation 72D (20 mg, 0.066 mmol) in a mixture of DME(Ratio: 2, Volume: 1.5 mL), EtOH (Ratio: 1.000, Volume: 0.750 mL), andwater (Ratio: 1.000, Volume: 0.750 mL) at room temperature in a sealedtube apparatus was added tetrakis(triphenylphosphine)palladium(0) (38.0mg, 0.033 mmol). The system was purged with nitrogen, sealed, and heatedto 90° C. for 12 h. The reaction mixture was diluted with MeOH,filtered, and concentrated. The residue was diluted with DMF and thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Gradient: 10-100% B over 25 minutes,then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containingthe desired product were combined and dried via centrifugal evaporationto afford the title compound (5.7 mg, 27%). ESI MS (M+H)⁺=317.1. HPLCPeak t_(r)=2.50 minutes. Purity=99%. HPLC Conditions: C. ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.60-8.69 (2 hr, m), 7.82 (1 hr, dd, J=8.05, 1.11Hz), 7.70 (1 hr, d, J=6.38 Hz), 7.58-7.67 (4 hr, m), 7.52-7.57 (1 hr,m), 7.32 (1 hr, d, J=8.05 Hz), 7.12-7.22 (2 hr, m), 3.86 (4 hr, s), 2.30(4 hr, s).

Example 737-(4-(Benzyloxy)pyrimidin-5-yl)-3-(2-methoxyphenyl)benzo[d]isoxazole

Preparation 73A: 3-(2-Methoxyphenyl)-7-(pyrimidin-5-yl)benzo[d]isoxazole

Pyrimidin-5-ylboronic acid (433 mg, 3.49 mmol) was placed in a sealedtube apparatus. Sodium carbonate (1542 mg, 14.55 mmol) and Preparation72D (885 mg, 2.91 mmol) in a mixture of DME (15 mL), water (7.50 mL) andEtOH (7.50 mL) were added at ambient temperature.Tetrakis(triphenylphosphine)palladium(0) (168 mg, 0.145 mmol) was thenadded and the system was purged with nitrogen, sealed, and heated to 90°C. for 12 h. The reaction mixture was diluted with MeOH, filtered, andconcentrated. The crude material was purified twice via silica gelchromatography 0-4% MeOH/DCM to afford the title compound (90 mg, 10%).ESI MS (M+H)⁺=303.9.

Preparation 73B:5-(3-(2-Methoxyphenyl)benzo[d]isoxazol-7-yl)pyrimidin-4-ol

To a stirring solution of Preparation 73A (90 mg, 0.297 mmol) in acetone(2 mL) at room temperature was added peracetic acid (0.062 mL, 0.297mmol). The system was heated to reflux for 2 h. The reaction mixture wascooled, the pH neutralized with 1N NaOH and extracted three times withDCM. The crude product was dissolved in a small amount of CH₂Cl₂ andcharged to a 4 g silica gel cartridge which was eluted with a 20 mingradient from 0% to 100% of ethyl acetate in dichloromethane to affordthe title compound (95 mg, 100%). ESI MS (M+H)⁺=320.9.

Preparation 73C: 7-(4-Chloropyrimidin-5-yl)-3-(2methoxyphenyl)benzo[d]isoxazole

A suspension of Preparation 73B (95 mg, 0.298 mmol) in POCl₃ (2.22 mL,23.80 mmol) was heated to 90° C. for 1 h. The volatiles were removed invacuo to afford the title compound (100 mg, 100%). ESI MS (M, M+2)⁺=337,339.

Example 73

To a stirring solution of phenylmethanol (1.494 mg, 0.014 mmol) in THF(Volume: 0.5 mL) at room temperature was added sodium hydride (1.658 mg,0.041 mmol). After 5 minutes, Preparation 73C (0.014 g, 0.041 mmol) wasadded and the reaction mixture was heated to 50° C. overnight. Thereaction mixture was cooled and diluted with 10 drops of water, and thesolvent removed with a stream of nitrogen. The remaining residue wasdissolved in DMF and the crude material was purified via preparativeLC/MS with the following conditions: Column: Waters XBridge C18, 19×250mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford the titlecompound (1.6 mg, 28%). ESI MS (M+H)⁺=410.0. HPLC Peak t_(r)=3.07minutes. Purity >99%. HPLC Conditions: B. ¹H NMR (500 MHz, MeOD) δ ppm8.80 (1 hr, s), 8.77 (1 hr, s), 7.69-7.80 (1 hr, m), 7.52-7.57 (1 hr,m), 7.36-7.44 (1 hr, m), 7.25-7.34 (1 hr, m), 7.09-7.18 (1 hr, m), 5.56(1 hr, s), 3.87 (1 hr, s).

Example 747-(4-(2-Fluoroethoxy)pyrimidin-5-yl)-3-(2-methoxyphenyl)benzo[d]isoxazole

To a stirring solution of 2-fluoroethanol (0.885 mg, 0.014 mmol) in THF(Volume: 0.5 mL) at room temperature was added sodium hydride (4.97 mg,0.124 mmol). After 5 minutes, Preparation 73C (0.014 g, 0.041 mmol) wasadded and the reaction mixture was heated to 50° C. overnight. Thereaction mixture was cooled and diluted with 10 drops of water, and thesolvent removed with a stream of nitrogen. The remaining residue wasdissolved in DMF and the crude material was purified via preparativeLC/MS with the following conditions: Column: Waters XBridge C18, 19×250mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford the titlecompound (1.3 mg, 26%). ESI MS (M+H)⁺=366.0. HPLC Peak t_(r)=2.52minutes. Purity >99%. HPLC Conditions: B. ¹H NMR (500 MHz, MeOD) δ ppm8.82 (1 hr, s), 8.78 (1 hr, s), 7.82 (1 hr, dd, J=7.49, 1.11 Hz), 7.76(1 hr, dd, J=8.05, 1.11 Hz), 7.60 (1 hr, dd, J=7.63, 1.80 Hz), 7.52-7.56(1 hr, m), 7.41-7.47 (1 hr, m), 7.16 (1 hr, d, J=8.32 Hz), 7.11 (1 hr,t, J=7.49 Hz), 4.73-4.83 (3 hr, m), 3.87 (3 hr, s).

Example 757-(4-Isopropoxypyrimidin-5-yl)-3-(2,2,2-trifluoroethoxy)benzo[d]isoxazole

Preparation 75A: 2-Fluoro-3-(pyrimidin-5-yl)benzonitrile

A sealed tube apparatus was charged with a solution containing5-bromopyrimidine (1 g, 6.29 mmol), sodium carbonate (3.33 g, 31.4mmol), and 3-cyano-2-fluorophenylboronic acid (1.037 g, 6.29 mmol) in amixture of DME (Ratio: 2, Volume: 31.4 ml), water (Ratio: 1.000, Volume:15.72 ml), and EtOH (Ratio: 1.000, Volume: 15.72 ml) at ambienttemperature. Tetrakis(triphenylphosphine)palladium(0) (0.363 g, 0.314mmol) was then added and the system was purged with nitrogen, sealed,and heated to 70° C. for 12 h. The vessel was cooled to room temperatureand diluted with EtOAc and water. The mixture was further diluted withbrine and extracted three times with EtOAc. The combined organics weredried over MgSO₄, filtered, and concentrated to give the crude product.The crude material was purified by flash chromatography on silica usingan ISCO machine (40 g SiO₂ column, 40 mL/min, 0-40% EtOAc/hexanes over15 minutes, t_(r)=8 minutes) to afford the title compound (300 mg, 24%).ESI MS (M+H)⁺=200.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.28 (1 hr, s),9.09 (2 hr, d, J=1.54 Hz), 8.02-8.12 (2 hr, m), 7.59 (1 hr, t, J=7.81Hz).

Preparation 75B: 7-(Pyrimidin-5-yl)benzo[d]isoxazol-3-amine

A mixture of Preparation 75A (300 mg, 1.506 mmol), N-hydroxyacetamide(339 mg, 4.52 mmol), and potassium carbonate (1.249 g, 9.04 mmol) in DMF(6.56 mL) and water (0.94 mL) was stirred at 80° C. for 3 hr. The vesselwas allowed to cool to room temperature and the mixture was filteredthrough a fritted funnel, and the filter cake was washed with EtOAc. Thelayers of the filtrate were separated, and the aqueous phase wasextracted three times with EtOAc. The organic extracts were combined,washed with water and brine then dried over anhydrous sodium sulfate.The slurry was filtered, concentrated, and further dried under highvacuum to afford the title compound (240 mg, 75%) as a yellow residue.ESI MS (M+H)⁺=213.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.32 (2 hr, s),9.25 (1 hr, s), 7.98 (2 hr, ddd, J=13.31, 7.59, 1.10 Hz), 7.45 (1 hr, t,J=7.59 Hz), 6.61 (2 hr, s).

Preparation 75C: 3-Chloro-7-(pyrimidin-5-yl)benzo[d]isoxazole

A solution of Preparation 75B (270 mg, 1.272 mmol) in concentratedhydrochloric acid, 37% (Volume: 13.3 mL) was cooled to 0° C. was treatedwith sodium nitrite (92 mg, 1.336 mmol). The reaction mixture wasstirred at 0° C. for 1 hr, and then at ambient temperature for 2 hr. Themixture was poured into a solution of saturated aqueous NH₄Cl (50 mL). Ayellow solid precipitated and the suspension was allowed to stir at roomtemperature overnight. The reaction mixture was neutralized with solidNaHCO₃ (52 g+5 g), then diluted with DCM. The layers were separated andthe aqueous phase was extracted with DCM five times. The organicextracts were combined, dried over Na₂SO₄, filtered, and concentrated toafford a yellow residue. The crude material was dissolved in a minimalamount of DCM and purified via silica gel chromatography using an ISCOmachine (80 g column, 60 mL/min, 50-70% EtOAc in hexanes over 25 min,t_(r)=12 min) to give the title compound (50 mg, 0.216 mmol, 16.97%yield) as a white solid. ESI MS (M, M+2)⁺=231, 233.

Preparation 75D:7-(Pyrimidin-5-yl)-3-(2,2,2-trifluoroethoxy)benzo[d]isoxazole

To a stirring solution of 2,2,2-trifluoroethanol (43.2 mg, 0.432 mmol)in DMF (1 mL) at room temperature was added sodium hydride (10.36 mg,0.432 mmol). After 3 minutes, Preparation 75C (50 mg, 0.216 mmol) wasadded. The mixture was allowed to stir until judged complete by HPLC.The reaction mixture was allowed to cool to room temperature, at whichpoint it was diluted with water and extracted twice with EtOAc. Theorganics were washed twice with 10% aq. LiCl and then dried over Na₂SO₄.Filtration and concentration afforded the title compound (61 mg, 96%).ESI MS (M+H)⁺=296.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.33 (2 hr, s),9.28 (1 hr, s), 8.16 (1 hr, dd, J=7.48, 1.10 Hz), 7.90-7.98 (2 hr, m),7.53-7.64 (1 hr, m), 5.26 (2 hr, q, J=8.66 Hz).

Preparation 75E:5-(3-(2,2,2-Trifluoroethoxy)benzo[d]isoxazol-7-yl)pyrimidin-4-ol

To a stirring solution of Preparation 75D (61 mg, 0.207 mmol) in acetone(2 mL) at room temperature was added peracetic acid (0.043 mL, 0.207mmol). The reaction mixture was heated to reflux. After 2 hours ofheating at 60° C., the reaction mixture was allowed to cool to roomtemperature, the pH was neutralized with 1N NaOH, and extracted threetimes with DCM. The crude product was dissolved in a small amount of DCMand charged to a 4 g silica gel cartridge which was eluted with a 20 mingradient from 0% to 100% of ethyl acetate in DCM to afford the titlecompound (21 mg, 33%). ESI MS (M+H)⁺=312.0. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.40 (1 hr, s), 8.32 (1 hr, s), 8.09 (1 hr, d, J=7.48 Hz), 7.81 (1hr, s), 7.49 (1 hr, t, J=7.70 Hz), 5.23 (2 hr, q, J=8.66 Hz).

Preparation 75F:7-(4-Chloropyrimidin-5-yl)-3-(2,2,2-trifluoroethoxy)benzo[d]isoxazole

A suspension of Preparation 75E (21 mg, 0.067 mmol) in POCl₃ (0.503 mL,5.40 mmol) was heated to 90° C. for 1 h. The volatile solvents wereremoved in vacuo to afford the title compound (22 mg, 100%). ESI MS (M,M+2)⁺=329.0, 331.0. ¹H NMR (400 MHz, THF) δ ppm 9.13 (1 hr, s), 8.97 (1hr, s), 7.92 (1 hr, dd, J=7.92, 0.88 Hz), 7.75-7.83 (1 hr, m), 7.54 (1hr, t, J=7.59 Hz), 5.06 (2 hr, q, J=8.36 Hz).

Example 75

To a stirring solution of propan-2-ol (9.92 mg, 0.165 mmol) in THF(Volume: 0.5 mL) at room temperature was added sodium hydride (3.96 mg,0.099 mmol). After 5 minutes, a solution of Preparation 75F (10.88 mg,0.033 mmol) in THF (Volume: 0.5 mL) was added. The mixture was allowedto stir until judged complete by HPLC. The reaction was quenched with 5drops of water. The reaction mixture was filtered. The filtrate wasconcentrated, diluted with DMF, and purified via preparative LC/MS withthe following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μmparticles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles;Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; MobilePhase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient:35-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation to afford the title compound (1.3 mg, 10%).ESI MS (M+H)⁺=354.0. HPLC Peak t_(r)=2.89 minutes. Purity=93%. HPLCConditions: B. ¹H NMR (400 MHz, MeOD) δ ppm 7.92 (1 hr, s), 7.82 (1 hr,s), 6.94 (2 hr, d, J=7.92 Hz), 6.75 (1 hr, s), 6.56-6.69 (1 hr, m), 4.72(1 hr, quin, J=6.22 Hz), 4.08 (2 hr, q, J=8.14 Hz), 0.52 (5 hr, d,J=6.16 Hz).

Example 763-(2-Methoxyphenyl)-7-(4-(2-morpholinoethoxy)pyrimidin-5-yl)benzo[d]isoxazole

To a stirring solution of 2-morpholinoethanol (0.016 g, 0.124 mmol) inTHF (Volume: 0.5 mL) at room temperature was added sodium hydride (4.97mg, 0.124 mmol). After 5 minutes, Preparation 73C (0.014 g, 0.041 mmol)was added and the reaction mixture was heated to 50° C. overnight. Thereaction mixture was diluted with 10 drops of water and concentrated.The remaining residue was dissolved in DMF and the crude material waspurified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: WatersXBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (0.9 mg, 5%). ESI MS(M+H)⁺=433.3. HPLC Peak t_(r)=1.79 minutes. Purity=94%. HPLC Conditions:E. ¹H NMR (400 MHz, MeOD) δ ppm 8.82 (1 hr, s), 8.71 (1 hr, s), 7.78 (1hr, dd, J=8.03, 0.99 Hz), 7.71 (1 hr, dd, J=7.37, 0.99 Hz), 7.58-7.64 (1hr, m), 7.46 (1 hr, t, J=7.70 Hz), 7.06-7.20 (2 hr, m), 4.76 (2 hr, t,J=4.84 Hz), 3.88 (3 hr, s), 3.69 (4 hr, t, J=4.18 Hz), 2.99-3.17 (2 hr,m), 2.73 (3 hr, br. s.).

Example 773-(2-Methoxyphenyl)-7-(4-(pyridazin-3-ylmethoxy)pyrimidin-5-yl)benzo[d]isoxazole

To a stirring solution of pyridazin-3-ylmethanol (0.014 g, 0.124 mmol)in THF (Volume: 0.5 mL) at room temperature was added sodium hydride(4.97 mg, 0.124 mmol). After 5 minutes, Preparation 73C (0.014 g, 0.041mmol) was added and the reaction mixture was heated at 50° C. overnight.The reaction mixture was diluted with 10 drops of water andconcentrated. The resulting residue was dissolved in DMF, filtered, andpurified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: WatersXBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (1.1 mg, 6%). ESI MS(M+H)⁺=412.0. HPLC Peak t_(r)=2.12 minutes. Purity=93%. HPLC Conditions:B. ¹H NMR (400 MHz, MeOD) δ ppm 9.08 (1 hr, dd, J=4.95, 1.65 Hz), 8.81(1 hr, s), 8.78 (1 hr, s), 7.73-7.80 (2 hr, m), 7.57-7.66 (2 hr, m),7.41-7.49 (1 hr, m), 7.16 (1 hr, d, J=8.14 Hz), 7.12 (1 hr, td, J=7.54,0.99 Hz), 5.88 (1 hr, s), 3.87 (2 hr, s).

Example 783-(2-Methoxyphenyl)-7-(4-(pyridazin-3-ylmethoxy)pyrimidin-5-yl)benzo[d]isoxazole

Preparation 78A:3-(2-Methoxyphenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole

A vial was charged with bis(acetonitrile)palladium(II) chloride (3.41mg, 0.013 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(10.80 mg, 0.026 mmol), and Preparation 72D (200 mg, 0.658 mmol). Thevial was capped with a rubber septum and then evacuated and backfilledwith N₂ (this sequence was carried out a total of 2 times). Dioxane(Volume: 394 μl) was added via syringe, through the septum, followed bythe addition of triethylamine (275 μl, 1.973 mmol) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (143 μl, 0.986 mmol). The septumwas then replaced with a Teflon screw valve, and the vial sealed. Thereaction mixture was heated at 110° C. After 13 hr, the reaction mixturewas allowed to cool to room temperature. The reaction mixture wasfiltered through a disposable fritted funnel and the filter cake washedwith CH₂Cl₂. The filtrate was concentrated to afford the title compoundas a yellow-green residue (231 mg, 100%).

Example 78

A pressure vessel was charged with Preparation 78A (0.035 g, 0.1 mmol),Preparation 12A (0.040 g, 0.130 mmol), and sodium carbonate (0.053 g,0.500 mmol). The vessel was then charged with DME (Ratio: 2, Volume: 1.5mL), water (Ratio: 1.000, Volume: 0.750 mL), and EtOH (Ratio: 1.000,Volume: 0.750 mL) at room temperature. To this mixture was addedtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol) and thesystem was purged with nitrogen and sealed. The vessel was heated at 90°C. for 12 h. The mixture was cooled to room temperature, diluted withMeOH, filtered and concentrated. The resulting residue was diluted withDMF and the crude material was purified via preparative LC/MS with thefollowing conditions: Column: Waters XBridge C18, 19×250 mm, 5-μmparticles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles;Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; MobilePhase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient:35-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation to afford the title compound (3.9 mg, 9%).ESI MS (M+H)⁺=402.0. HPLC Peak t_(r)=2.85 minutes. Purity=95%. HPLCConditions: B. ¹H NMR (400 MHz, MeOD) δ ppm 8.91 (1 hr, s), 8.84 (1 hr,s), 7.74-7.82 (2 hr, m), 7.60 (1 hr, dd, J=7.48, 1.54 Hz), 7.51-7.56 (1hr, m), 7.40-7.49 (1 hr, m), 7.08-7.20 (2 hr, m), 4.99 (2 hr, q, J=8.51Hz), 3.87 (3 hr, s).

Example 79 7-(4-Chloropyridin-3-yl)-3-(2-methoxyphenyl)benzo[d]isoxazole

A pressure vessel was charged with 4-chloro-3-iodopyridine (31.1 mg,0.130 mmol), Preparation 78A (35.1 mg, 0.100 mmol), and sodium carbonate(53.0 mg, 0.500 mmol). DME (Ratio: 2, Volume: 1.5 mL), water (Ratio:1.000, Volume: 0.750 mL), and EtOH (Ratio: 1.000, Volume: 0.750 mL) werethen added at room temperature. To this mixture was addedtetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 μmol) and thesystem was purged with nitrogen and sealed. The vessel was heated at 90°C. for 12 hr. The reaction mixture was diluted with MeOH, filtered, andconcentrated. The resulting oil was diluted with DMF and the crudematerial was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (2.8 mg, 8%). ESI MS(M+H)⁺=337.0. HPLC Peak t_(r)=2.69 minutes. Purity=97%. HPLC Conditions:B. ¹H NMR (400 MHz, MeOD) δ ppm 8.67 (1 hr, s), 8.54 (1 hr, d, J=5.50Hz), 7.81 (1 hr, dd, J=8.03, 0.99 Hz), 7.58-7.67 (3 hr, m), 7.53 (1 hr,d, J=1.76 Hz), 7.43-7.50 (1 hr, m), 7.04-7.21 (2 hr, m), 3.88 (3 hr, s).

Example 80 7-(Isoquinolin-4-yl)-3-(2-methoxyphenyl)benzo[d]isoxazole

A pressure tube was charged with Preparation 72D (30 mg, 0.099 mmol),isoquinolin-4-ylboronic acid (20.47 mg, 0.118 mmol), and sodiumcarbonate (52.3 mg, 0.493 mmol). The vessel was then charged with water(Ratio: 1.000, Volume: 0.750 mL), DME (Ratio: 2, Volume: 1.5 mL), andEtOH (Ratio: 1.000, Volume: 0.750 mL) at room temperature. To thisslurry was added tetrakis(triphenylphosphine)palladium(0) (57.0 mg,0.049 mmol) and the system was purged with nitrogen and sealed. Thevessel was heated at 90° C. for 12 hr. The reaction mixture was dilutedwith MeOH, filtered, and concentrated. The resulting oil was dilutedwith DMF and the crude material was purified via preparative LC/MS withthe following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μmparticles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to afford the title compound (1.9mg, 5%). ESI MS (M+H)⁺=353.0. HPLC Peak t_(r)=2.80 minutes. Purity=99%.HPLC Conditions: B. ¹H NMR (400 MHz, MeOD) δ ppm 9.30 (1 hr, s), 8.56 (1hr, s), 8.12-8.23 (1 hr, m), 7.84 (1 hr, dd, J=8.14, 1.10 Hz), 7.73-7.78(3 hr, m), 7.66-7.73 (2 hr, m), 7.62 (1 hr, dd, J=7.59, 1.65 Hz),7.48-7.55 (2 hr, m), 7.18 (1 hr, d, J=8.14 Hz), 7.12 (1 hr, td, J=7.48,0.88 Hz), 3.91 (4 hr, s).

Example 817-(4-(2,2-Difluoroethoxy)pyrimidin-5-yl)-3-(2-methoxyphenyl)benzo[d]isoxazole

To a stirring solution of 2,2-difluoroethanol (1.134 mg, 0.014 mmol) inTHF (Volume: 0.5 mL) at room temperature was added sodium hydride (4.97mg, 0.124 mmol). After 5 minutes, Preparation 73C (0.014 g, 0.041 mmol)was added and the reaction mixture was heated at 50° C. overnight. Thereaction mixture was diluted with 10 drops of water and concentrated.The resulting residue was dissolved in DMF, filtered, and the crudematerial was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (0.5 mg, 8%). ESI MS(M+H)⁺=384.0. HPLC Peak t_(r)=2.65 minutes. Purity=89%. HPLC Conditions:B.

Example 823-(2-Methoxyphenyl)-7-(4-methylpyrimidin-5-yl)benzo[d]isoxazole

A pressure vessel was charged with Preparation 78A (35.1 mg, 0.100mmol), 5-bromo-4-methylpyrimidine (22.49 mg, 0.130 mmol), and sodiumcarbonate (53.2 mg, 0.502 mmol). To this vessel was then added DME(Ratio: 2, Volume: 1.5 mL), EtOH (Ratio: 1.000, Volume: 0.750 mL), andwater (Ratio: 1.000, Volume: 0.750 mL) at room temperature. To thisslurry was added tetrakis(triphenylphosphine)palladium(0) (58.0 mg,0.050 mmol) and the system was purged with nitrogen and sealed. Thevessel was heated at 90° C. for 12 hr. The reaction mixture was dilutedwith MeOH, filtered, and concentrated. The resulting oil was dilutedwith DMF and the crude material was purified via preparative LC/MS withthe following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μmparticles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation. The material was further purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;Gradient: 15-55% B over 25 minutes, then a 10-minute hold at 55% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to afford the title compound (4.0mg, 12%). ESI MS (M+H)⁺=318.1. HPLC Peak t_(r)=2.28 minutes. Purity=93%.HPLC Conditions: B. ¹H NMR (500 MHz, MeOD) δ ppm 9.10 (1 hr, s), 8.72 (1hr, s), 7.83 (1 hr, dd, J=7.91, 1.25 Hz), 7.61 (1 hr, dd, J=7.49, 1.66Hz), 7.54 (1 hr, d, J=1.66 Hz), 7.45-7.52 (1 hr, m), 7.17 (1 hr, d,J=8.05 Hz), 7.12 (1 hr, t, J=7.49 Hz), 3.88 (3 hr, s), 2.55 (3 hr, s).

Example 833-(2-Methoxyphenyl)-7-(4-morpholinopyrimidin-5-yl)benzo[d]isoxazole

A pressure vessel was charged with Preparation 78A (35.1 mg, 0.100mmol), Preparation 16A (37.8 mg, 0.130 mmol), and sodium carbonate (53.2mg, 0.502 mmol). To this vessel was then added DME (Ratio: 2, Volume:1.5 mL), EtOH (Ratio: 1.000, Volume: 0.750 mL), and water (Ratio: 1.000,Volume: 0.750 mL) at room temperature. To this slurry was addedtetrakis(triphenylphosphine)palladium(0) (58.0 mg, 0.050 mmol) and thesystem was purged with nitrogen and sealed. The vessel was heated at 90°C. for 12 hr. The reaction mixture was diluted with MeOH, filtered, andconcentrated. The resulting oil was diluted with DMF and the crudematerial was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound (4.2 mg, 11%). ESI MS(M+H)⁺=389.1. HPLC Peak t_(r)=2.25 minutes. Purity >99%. Conditions: B.¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.70 (1 hr, s), 8.42 (1 hr, s),7.74-7.84 (2 hr, m), 7.58-7.67 (2 hr, m), 7.50-7.56 (1 hr, m), 7.32 (1hr, d, J=8.05 Hz), 7.07-7.22 (1 hr, m), 3.85 (2 hr, s), 3.37-3.47 (3 hr,m), 3.31 (19 hr, s), 3.19-3.28 (3 hr, m).

Example 843-(2-Methoxyphenyl)-7-(pyrrolo[1,2-c]pyrimidin-4-yl)benzo[d]isoxazole

A pressure vessel was charged with Preparation 78A (35.1 mg, 0.100mmol), Preparation 14C (19.70 mg, 0.100 mmol), and sodium carbonate(53.2 mg, 0.502 mmol). To the vessel was then added DME (Ratio: 2,Volume: 1.5 mL), EtOH (Ratio: 1.000, Volume: 0.750 mL), and water(Ratio: 1.000, Volume: 0.750 mL) at room temperature. To this slurry wasadded tetrakis(triphenylphosphine)palladium(0) (58.0 mg, 0.050 mmol) andthe system was purged with nitrogen and sealed. The vessel was heated at90° C. for 12 hr. The reaction mixture was diluted with MeOH, filtered,and concentrated. The resulting oil was diluted with DMF and the crudematerial was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: Waters XBridge C18, 19×250 mm,5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA;Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 15-60%B over 25 minutes, then a 10-minute hold at 60% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (1.6 mg, 4.7%). ESIMS (M+H)⁺=342.0. HPLC Peak t_(r)=2.70 minutes. Purity >99%. HPLCConditions: B.

Example 857-(4-Methylpyridin-3-yl)-3-(3,3,3-trifluoropropyl)benzo[d]isoxazole

Preparation 85A: (3,3,3-Trifluoropropyl)magnesium bromide

To a 3-necked 250 mL flask was added magnesium (2.75 g, 113 mmol) and astir bar. The magnesium was stirred vigorously under vacuum for 2 days.The flask was then placed under with N₂ and charged with ethyl ether(100 mL). The 3-necked flask was also equipped with a condenser andheated at 50° C. 1,2-Dibromoethane (0.1 mL) was added and followed bythe addition of a small amount of 4-bromo-1,1,1-trifluorobutane in Et₂O.After 5-10 min, the heat source was removed and3-bromo-1,1,1-trifluoropropane (10 g, 56.5 mmol) in 20 mL of Et₂O wasadded slowly via syringe. Upon addition of all of the4-bromo-1,1,1-trifluorobutane, the reaction mixture was heated at 50° C.for another 30 min. The concentration was of the solution was determinedto be 0.47M and the material was stored under N₂ at −20° C.

Preparation 85B: 1-(3-Bromo-2-fluorophenyl)-4,4,4-trifluorobutan-1-ol

To a solution of 3-bromo-2-fluorobenzaldehyde (500 mg, 2.463 mmol) inTHF (10 mL) at −78° C. was added Preparation 85A (10 mL, 2.463 mmol).The reaction mixture was stirred at −78° C. for 1 h, then allowed towarm to room temperature and stirred for 6 hr. The reaction mixture wasdiluted with saturated aqueous NH₄Cl and EtOAc. The organic phase wasseparated and washed with brine, dried over MgSO₄, filtered andconcentrated to give the title compound (700 mg, 1.162 mmol, 47.2%yield) as yellow liquid.

Preparation 85C: 1-(3-Bromo-2-fluorophenyl)-4,4,4-trifluorobutan-1-one

To a solution of Preparation 85B (680 mg, 2.259 mmol) in CH₂Cl₂ (10 mL)at room temperature was added Dess-Martin periodinane (1916 mg, 4.52mmol). The suspension was stirred at room temperature overnight, thendiluted with an aqueous solution of 10% Na₂S₂O₃ and saturated NaHCO₃.The mixture was stirred for 30 min until a clear solution formed. Theorganic phase was separated and washed with brine, dried over MgSO₄,filtered, and concentrated to give the title compound (650 mg, 2.130mmol, 94% yield) as yellow liquid.

Preparation 85D:(Z)-1-(3-Bromo-2-fluorophenyl)-4,4,4-trifluorobutan-1-one oxime

To a solution of Preparation 85C (650 mg, 2.173 mmol) in pyridine (10mL) at room temperature was added hydroxylamine hydrochloride (227 mg,3.26 mmol). The reaction mixture was stirred at 70° C. for 2 h. Thesolvent was evaporated and the resulting residue was partitioned betweenEtOAc and 1N HCl. The organic phase was separated, washed with brine,dried over MgSO₄, filtered, and concentrated to give the title compound(680 mg, 2.057 mmol, 95% yield) as light brown liquid. ESI MS(M+H)⁺314.0.

Preparation 85E: 7-Bromo-3-(3,3,3-trifluoropropyl)benzo[d]isoxazole

To the suspension of NaH (35.7 mg, 0.892 mmol) in THF (4 mL) at roomtemperature was added Preparation 85D (200 mg, 0.446 mmol) in DMF (4.00mL) dropwise. The reaction mixture was heated at 70° C. for 1 h.Additional NaH (35.7 mg, 0.892 mmol) was added and the reaction mixturewas stirred at 70° C. for 2 h. More NaH (35.7 mg, 0.892 mmol) was addedand the reaction mixture was stirred for another 30 min. The reactionmixture was cooled to room temperature and diluted with saturated NH₄Cland EtOAc. The organic phase was separated and washed with brine, driedover MgSO₄, and concentrated. Purification of the crude material bysilica gel chromatography using an ISCO machine (24 g column, 35 mL/min,0-50% EtOAc in hexanes over 25 min) gave the title compound (22 mg,0.074 mmol, 16.62% yield) as light brown liquid. ESI MS (M+H)⁺=295.9.

Example 85

To a suspension of 4-methylpyridin-3-ylboronic acid (12.29 mg, 0.090mmol) in DME (0.5 mL), EtOH (0.250 mL) and water (0.250 mL) were added7-bromo-3-(3,3,3-trifluoropropyl)benzo[d]isoxazole (22 mg, 0.075 mmol),followed by Na₂CO₃ (31.7 mg, 0.299 mmol). The reaction mixture waspurged with N₂ for 10 min, then tetrakis(triphenylphosphine)palladium(0)(4.32 mg, 3.74 μmol) was added and the reaction vessel was sealed andheated at 90° C. for overnight. The reaction mixture was allowed to coolto room temperature and then filtered. The filtrate was diluted withMeOH and purified via preparative LC/MS with the following conditions:Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column:Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: Waters XBridge C18, 19×250 mm,5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 25-60% B over 25 minutes, then a 15-minute hold at60% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford the titlecompound (1.5 mg, 6.8%). ESI MS (M+H)⁺=307.1. HPLC Peak t_(r)=2.44minutes. Purity >99%. HPLC Conditions: B.

Example 863-(4-Fluorophenyl)-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine

Preparation 86A: 3-Fluoro-4-iodopicolinonitrile

To a solution of diisopropylamine (2.80 ml, 19.66 mmol) in THF (Volume:201 ml) cooled to −78° C. was added n-butyllithium (7.86 ml, 19.66 mmol)dropwise. The dry ice/acetone bath was replaced with an ice water bathand reaction mixture was stirred at 0° C. for 25 min, and then re-cooledto −78° C. In a separate flask, a solution of 3-fluoropicolinonitrile(1.5 g, 12.29 mmol) in THF (50 mL) was cooled to −78° C., and then LDA(130 mL, 1.0 equiv) was added. The solution turned dark red. After 35min, iodine (3.43 g, 13.51 mmol) was added rapidly. The reaction mixturewas stirred for 45 min, then quenched with H₂O. Layers were separatedand the aqueous phase extracted with CH₂Cl₂ (2×). Organics combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (80 g column, 60 mL/min, 0-20%EtOAc in hexanes over 23 min, t_(r)=18 min) gave the title compound (1.7g, 6.79 mmol, 55.2% yield) as a brown solid.

Preparation 86B: 3′-Fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile

A vial containing a mixture of 3-fluoro-4-iodopicolinonitrile (0.150 g,0.605 mmol), 4-methylpyridin-3-ylboronic acid (0.174 g, 1.270 mmol), andcesium carbonate (0.414 g, 1.270 mmol) in dioxane (Ratio: 2.0, Volume:1.222 ml) and water (Ratio: 1.000, Volume: 0.611 ml) was degassed withN₂ for 5 min, then PdCl₂(dppf)-CH₂Cl₂Adduct (0.026 g, 0.032 mmol) wasadded. The solution was heated at 85° C. for 14 hr, then allowed to coolto room temperature. The crude material was dissolved in a minimalamount of CH₂Cl₂ to be chromatographed. Purification of the crudematerial by silica gel chromatography using an ISCO machine (40 gcolumn, 40 mL/min, 70-100% EtOAc in hexanes over 19 min, t_(r)=14 min)gave the title compound (24 mg, 0.111 mmol, 18.42% yield) as a purpleresidue. ESI MS (M+H)⁺=214.1.

Preparation 86C:(3′-Fluoro-4-methyl-3,4′-bipyridin-2′-yl)(4-fluorophenyl)methanone

To a solution of 3′-fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile(0.029 g, 0.136 mmol) in THF (Volume: 0.680 ml) cooled to 0° C. wasadded (4-fluorophenyl)magnesium bromide (0.170 ml, 0.340 mmol). Thereaction mixture was allowed to stir at room temperature for 5 hr. Waterand ice were carefully added, followed by acidification with 6 M HCl.After stirring for 20 min, CH₂Cl₂ was added and the pH was adjusted to8.5 with aqueous 4 M NaOH. The layers were separated and the aqueousphase was extracted with CH₂Cl₂ (9×). The organics layers were combined,dried over Na₂SO₄, filtered, and concentrated to afford a residue. Thecrude material was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (12 g column, 30 mL/min, 70-90%EtOAc in hexanes over 14 min, tr=8 min) gave the title compound (29 mg,0.089 mmol, 65.3% yield). ESI MS (M+H)⁺=311.1.

Preparation 86D:(Z)-(3′-Fluoro-4-methyl-3,4′-bipyridin-2′-yl)(4-fluorophenyl)methanoneoxime

A solution of(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)(4-fluorophenyl)methanone(0.029 g, 0.093 mmol) and hydroxylamine hydrochloride (0.044 g, 0.636mmol) in pyridine (Volume: 0.467 ml) was refluxed for 1.5 hr, allowed tocool to room temperature, and then concentrated in vacuo. The crudematerial was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed (required a few drops of MeOH). Purification of thecrude material by silica gel chromatography using an ISCO machine (4 gcolumn, 18 mL/min, 80-100% EtOAc in hexanes over 12 min, t_(r)=2.5 min)gave the title compound (22 mg, 0.068 mmol, 72.4% yield) as a yellowsolid. ESI MS (M+H)⁺=326.2.

Example 86

To a suspension of sodium hydride (4.60 mg, 0.115 mmol) in THF (Ratio:1.8, Volume: 869 μl) was added dropwise(Z)-(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)(4-fluorophenyl)methanoneoxime (22 mg, 0.068 mmol) in DMF (Ratio: 1.0, Volume: 483 μl) slowly.The reaction mixture was heated at 70° C. for 3 hr, and then allowed tocool to room temperature. The reaction was quenched with H₂O. Thereaction mixture was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, concentrated, and further driedunder high vacuum to afford a yellow solid. The crude material wasdissolved in a minimal amount of CH₂Cl₂ to be chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (4 g column, 18 mL/min, 60-100% EtOAc in hexanes over 15min, t_(r)=5 min) gave the title compound (9.6 mg, 0.030 mmol, 44.2%yield) as a white solid. ESI MS (M+H)⁺=306.1. HPLC Peak t_(r)=2.84minutes. Purity=95%. HPLC Conditions: C.

Example 87 3-Chloro-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine

Preparation 87A: 7-(4-Methylpyridin-3-yl)isoxazolo[4,5-b]pyridin-3-amine

A mixture of 3′-fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile (0.057g, 0.267 mmol), N-hydroxyacetamide (0.060 g, 0.802 mmol), and potassiumcarbonate (0.222 g, 1.604 mmol) in DMF (Ratio: 7.0, Volume: 1.170 ml)and water (Ratio: 1.000, Volume: 0.167 ml) was stirred at 80° C. for 3hr. The reaction mixture was filtered through a disposable frittedfunnel. The filter cake was washed with EtOAc. Layers in the filtratewere separated and the aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, concentrated,and further dried under high vacuum to afford the title compound as abrown solid (49 mg, 0.206 mmol, 77% yield). ESI MS (M+H)⁺=227.1.

Example 87

To a solution of 7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridin-3-amine(0.049 g, 0.217 mmol) in concentrated hydrochloric acid, 37% (Volume:2.256 ml) cooled to 0° C. was added sodium nitrite (0.016 g, 0.227mmol). The reaction mixture was stirred at 0° C. for 1 hr, and thenallowed to stir at room temperature for 2 hr. The mixture was pouredinto a solution of saturated aqueous NH₄Cl (2.2 mL). A yellow solidprecipitated, then the mixture became homogenous. The suspension wasallowed to stir at room temperature overnight. The reaction mixture wasneutralized with solid NaHCO₃ (2.3 g+222 mg), then diluted with CH₂Cl₂.Layers were separated and the aqueous phase was extracted with CH₂Cl₂(5×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was dissolvedin a minimal amount of CH₂Cl₂ to be chromatographed. Purification of thecrude material by silica gel chromatography using an ISCO machine (4 gcolumn, 18 mL/min, 50-60% EtOAc in hexanes over 19 min, t_(r)=9 min)gave the title compound (16 mg, 0.064 mmol, 29.8% yield) as a whitesolid. ESI MS (M+H)⁺=246.0. HPLC Peak t_(r)=1.31 minutes. Purity=99%.HPLC Conditions: C.

Example 88 7-(4-Methylpyridin-3-yl)-3-morpholinoisoxazolo[4,5-b]pyridine

To a suspension of3-chloro-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine (0.0069 g,0.028 mmol) and morpholine (0.025 ml, 0.281 mmol) in DMSO (Volume: 0.100ml) was added cesium carbonate (0.027 g, 0.084 mmol). The vial wassealed, heated at 90° C. for 4 hr, and then allowed to cool to roomtemperature. The reaction mixture was filtered through a disposablefritted funnel and the filter cake washed with CH₂Cl₂. The solvent wasconcentrated to afford a yellow liquid, which was further dried underhigh vacuum overnight. The crude material was dissolved in a minimalamount of CH₂Cl₂ to be chromatographed. Purification of the crudematerial by silica gel chromatography using an ISCO machine (4 g column,18 mL/min, 70-100% EtOAc in hexanes over 14 min, t_(r)=4.5 min) gave7-(4-methylpyridin-3-yl)-3-morpholinoisoxazolo[4,5-b]pyridine (6.5 mg,0.021 mmol, 76% yield) as a white solid. ESI MS (M+H)⁺=297.2. HPLC Peakt_(r)=1.56 minutes. Purity=97%. HPLC Conditions: C.

Example 89 7-(4-Methylpyridin-3-yl)-3-phenylisoxazolo[4,5-b]pyridine

Preparation 89A:(3′-Fluoro-4-methyl-3,4′-bipyridin-2′-yl)(phenyl)methanone

To a solution of 3′-fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile(0.027 g, 0.127 mmol) in THF (Volume: 0.633 ml) cooled to 0° C. wasadded phenylmagnesium bromide (0.317 ml, 0.317 mmol). The reactionmixture was allowed to stir at room temperature overnight. Water and icewere carefully added, followed by acidification with 6 M HCl. Afterstirring for 1 hr, CH₂Cl₂ was added and the pH was adjusted to 8.5 withaqueous 4 M NaOH. The layers were separated and the aqueous phase wasextracted with CH₂Cl₂ (5×). Organics combined, dried over Na₂SO₄,filtered, and concentrated to afford a purple residue. The crudematerial was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (4 g column, 18 mL/min, 70-100%EtOAc in hexanes over 19 min, t_(r)=6.5 min) gave the title compound(0.025 g, 0.081 mmol, 64.2% yield) as an orange residue. ESI MS(M+H)⁺=293.1.

Preparation 89B:(Z)-(3′-Fluoro-4-methyl-3,4′-bipyridin-2′-yl)(phenyl)methanone oxime

A solution of (3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)(phenyl)methanone(0.025 g, 0.086 mmol) and hydroxylamine hydrochloride (0.040 g, 0.582mmol) in pyridine (Volume: 0.428 ml) was refluxed for 2.5 hr, allowed tocool to room temperature, and then concentrated in vacuo. The crudematerial was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed (required a few drops of MeOH). Purification of thecrude material by silica gel chromatography using an ISCO machine (4 gcolumn, 18 mL/min, 80-100% EtOAc in hexanes over 10 min, t_(r)=0.3, 1.5,2 min) gave the title compound (23.7 mg, 0.076 mmol, 89% yield) as ayellow residue. ESI MS (M+H)⁺=308.2.

Example 89

To a suspension of sodium hydride (5.24 mg, 0.131 mmol) in THF (Ratio:1.8, Volume: 992 μl) was added dropwise(Z)-(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)(phenyl)methanone oxime(23.7 mg, 0.077 mmol) in DMF (Ratio: 1.0, Volume: 551 μl) slowly. Thereaction mixture was heated at 70° C. for 3 hr, and then allowed to coolto room temperature. The reaction was quenched with H₂O. The reactionmixture was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, concentrated, and further dried under highvacuum to afford a yellow residue. The crude material was re-dissolvedin 1.5 mL DMF and purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-100% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 30-65% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (5.1 mg, 23%). ESI MS (M+H)⁺=288.1. HPLC Peakt_(r)=2.49 minutes. Purity >99%. HPLC Conditions: B.

Example 903-(5-Fluoro-2-methoxyphenyl)-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine

Preparation 90A:(5-Fluoro-2-methoxyphenyl)(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)methanone

To a solution of 3′-fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile(0.031 g, 0.145 mmol) in THF (Volume: 0.727 ml) cooled to 0° C. wasadded (5-fluoro-2-methoxyphenyl)magnesium bromide (0.727 ml, 0.363mmol). The reaction mixture was allowed to stir at room temperature.Water and ice were carefully added, followed by acidification with 6 MHCl. After stirring for 1 hr, CH₂Cl₂ was added and the pH was adjustedto 8.5 with aqueous 4 M NaOH. The layers were separated. The aqueousphase was extracted with CH₂Cl₂ (5×). Organics combined, dried overNa₂SO₄, filtered, and concentrated to afford a purple residue. The crudematerial was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (4 g column, 18 mL/min, 60-100%EtOAc in hexanes over 18 min, t_(r)=9 min) gave the title compound(0.024 g, 0.070 mmol, 48.0% yield) as an orange residue. ESI MS(M+H)⁺=340.2.

Preparation 90B:(Z)-(5-Fluoro-2-methoxyphenyl)(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)methanoneoxime

A solution of(5-fluoro-2-methoxyphenyl)(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)methanone(0.024 g, 0.071 mmol) and hydroxylamine hydrochloride (0.033 g, 0.480mmol) in pyridine (Volume: 0.353 ml) was refluxed for 3 hr, allowed tocool to room temperature, and then concentrated in vacuo. The crudematerial was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed (required a few drops of MeOH). Purification of thecrude material by silica gel chromatography using an ISCO machine (4 gcolumn, 18 mL/min, 0-95% EtOAc in hexanes over 15 min, t_(r)=0.5, 1.5.2.5 min) gave the title compound (22 mg, 0.061 mmol, 87% yield) as ayellow residue. ESI MS (M+H)⁺=356.1.

Example 90

To a suspension of sodium hydride (4.21 mg, 0.105 mmol) in THF (Ratio:1.8, Volume: 796 μl) was added dropwise(Z)-(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl) (phenyl)methanone oxime(23.7 mg, 0.077 mmol) in DMF (Ratio: 1.0, Volume: 442 μl) slowly. Thereaction mixture was heated at 70° C. for 3 hr, and then allowed to coolto room temperature. The reaction was quenched with H₂O. The reactionmixture was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, concentrated, and further dried under highvacuum to afford a yellow residue. The crude material was re-dissolvedin 1.5 mL DMF and purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; GuardColumn: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (4.6 mg, 22%). ESIMS (M+H)⁺=336.1. HPLC Peak t_(r)=2.28 minutes. Purity=98%. HPLCConditions: B.

Example 915-(3-(2-Chloro-4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-amine

Preparation 91A: 3-Fluoro-4-(pyrimidin-5-yl)picolinonitrile

A vial containing a mixture of 3-fluoro-4-iodopicolinonitrile (3.0 g,12.10 mmol), pyrimidin-5-ylboronic acid (5.23 g, 42.2 mmol), and cesiumcarbonate (8.28 g, 25.4 mmol) in dioxane (Ratio: 2.0, Volume: 24.44 ml)and water (Ratio: 1.000, Volume: 12.22 ml) was degassed with N₂ for 5min, then PdCl₂(dppf)-CH₂Cl₂Adduct (0.524 g, 0.641 mmol) was added. Thesolution was heated at 85° C. for 21 hr, and then allowed to cool toroom temperature. The reaction was quenched with water. The reactionmixture was diluted with EtOAc. The layers were separated and theaqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was dissolved in a minimal amount ofCH₂Cl₂ to be chromatographed. Purification of the crude material bysilica gel chromatography using an ISCO machine (120 g column, 85mL/min, 50-90% EtOAc in hexanes over 25 min, t_(r)=10 min) gave thetitle compound (1.089 g, 5.39 mmol, 44.5% yield) as an orange solid.

Preparation 91B:(2-Chloro-4-fluorophenyl)(3-fluoro-4-(pyrimidin-5-yl)pyridin-2-yl)methanone

To a solution of 2-chloro-4-fluoro-1-iodobenzene (0.307 g, 1.199 mmol)in THF (Volume: 1.622 ml) cooled to −10° C. was added isopropylmagnesiumchloride, 2M in THF (0.699 ml, 1.399 mmol) in one portion. After 30 min,3-fluoro-4-(pyrimidin-5-yl)picolinonitrile (0.200 g, 0.999 mmol) wasadded. The reaction mixture was stirred at −10° C. for 30 min, thenallowed to warm to room temperature and stirred overnight. Water and icewere carefully added, followed by acidification with 6 M HCl. Afterstirring for 1 hr, CH₂Cl₂ was added and the pH was adjusted to 8.5 withaqueous 4 M NaOH. The layers were separated. The aqueous phase wasextracted with CH₂Cl₂ (5×). Organics combined, dried over Na₂SO₄,filtered, and concentrated to afford an orange residue. The crudematerial was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (24 g column, 35 mL/min, 60-100%EtOAc in hexanes over 23 min, t_(r)=9 min) gave the title compound(0.029 g, 0.074 mmol, 7.44% yield) as an orange solid.

Preparation 91C:(Z)-(2-Chloro-4-fluorophenyl)(3-fluoro-4-(pyrimidin-5-yl)pyridin-2-yl)methanoneoxime

A solution of(2-chloro-4-fluorophenyl)(3-fluoro-4-(pyrimidin-5-yl)pyridin-2-yl)methanone(0.030 g, 0.090 mmol) and hydroxylamine hydrochloride (0.043 g, 0.615mmol) in pyridine (Volume: 0.452 ml) was refluxed for 3 hr, allowed tocool to room temperature, and then concentrated in vacuo. The crudematerial was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed (required a few drops of MeOH). Purification of thecrude material by silica gel chromatography using an ISCO machine (4 gcolumn, 18 mL/min, 0-100% EtOAc in hexanes over 11 min, t_(r)=0.4, 2min) gave the title compound (29 mg, 0.079 mmol, 88% yield) as a yellowresidue. ESI MS (M+H)⁺=347.0.

Preparation 91D:3-(2-Chloro-4-fluorophenyl)-7-(pyrimidin-5-yl)isoxazolo[4,5-b]pyridine

To a suspension of sodium hydride (5.69 mg, 0.142 mmol) in THF (Ratio:1.8, Volume: 1.075 ml) was added dropwise(Z)-(2-chloro-4-fluorophenyl)(3-fluoro-4-(pyrimidin-5-yl)pyridin-2-yl)methanoneoxime (0.029 g, 0.084 mmol) in DMF (Ratio: 1.0, Volume: 0.597 ml)slowly. The reaction mixture was heated at 70° C. for 3 hr, and thenallowed to cool to room temperature. The reaction was quenched with H₂O.The reaction mixture was extracted with EtOAc (3×). The organic phaseswere combined, dried over Na₂SO₄, filtered, concentrated, and furtherdried under high vacuum to afford a brown residue. The crude materialwas dissolved in a minimal amount of CH₂Cl₂ to be chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (4 g column, 18 mL/min, 0-80% EtOAc in hexanes over 15 min,t_(r)=3 min) gave the title compound (10.3 mg, 0.028 mmol, 33.9% yield)as a yellow solid. ESI MS (M+H)⁺=327.0.

Preparation 91E:5-(3-(2-Chloro-4-fluorophenypisoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-ol

To a vial charged with3-(2-chloro-4-fluorophenyl)-7-(pyrimidin-5-yl)isoxazolo[4,5-b]pyridine(4.8 mg, 0.015 mmol) in acetone (Volume: 100 μl) were added peroxyaceticacid (6.18 μl, 0.029 mmol) and sulfuric acid (1.632 μl, 0.029 mmol). Thereaction mixture was refluxed for 75 min, and then allowed to cool toroom temperature. The reaction mixture was neutralized with 4 M NaOH andextracted with CH₂Cl₂ (5×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford the title compound as ayellow residue (5.0 mg, 99%). ESI MS (M+H)⁺=343.0.

Preparation 91F:3-(2-Chloro-4-fluorophenyl)-7-(4-chloropyrimidin-5-yl)isoxazolo[4,5-b]pyridine

A suspension of5-(3-(2-chloro-4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-ol(5.0 mg, 0.015 mmol) in phosphorus oxychloride (100 μl, 1.073 mmol) washeated at 90° C. for 1 h, then allowed to cool to room temperature. Thesolvent was evaporated to give the title compound (5.3 mg, 100%).

Example 91

A vial was charged with 4-chloro-5-iodopyrimidine (10 mg, 0.042 mmol)and freshly prepared saturated NH₃/MeOH (300 μL, 0.015 mmol). Thereaction mixture was sealed with a Teflon lined screw cap and heated at90° C. for 2 hr, then allowed to cool to room temperature. The solventwas evaporated. The crude material was re-dissolved in 1.5 mL DMF andpurified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: WatersXBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: Waters XBridge C18, 19×250 mm,5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 5-40% B over 25 minutes, then a 15-minute hold at 40%B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford the titlecompound (0.9 mg, 18%). ESI MS (M+H)⁺=342.1. HPLC Peak t_(r)=1.44minutes. Purity=98%. HPLC Conditions: E.

Example 925-(3-(4-Fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-amine

Preparation 92A: 3-Fluoro-4-(pyrimidin-5-yl)picolinonitrile

A vial containing a mixture of 3-fluoro-4-iodopicolinonitrile (1.25 g,5.04 mmol), pyrimidin-5-ylboronic acid (1.249 g, 10.08 mmol), and cesiumcarbonate (3.45 g, 10.58 mmol) in dioxane (Ratio: 2.0, Volume: 10.18 ml)and water (Ratio: 1.000, Volume: 5.09 ml) was degassed with N₂ for 5min, then PdCl₂(dppf)-CH₂Cl₂Adduct (0.218 g, 0.267 mmol) was added. Thesolution was heated at 85° C. for 17 hr, and then allowed to cool toroom temperature. The reaction was quenched with water. The reactionmixture was diluted with EtOAc. The layers were separated and theaqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified by MPLC (80 g column, 60mL/min, 30-100% EtOAc in hexanes) to give the title compound (695 mg,3.44 mmol, 68.2% yield) as a pink solid. ESI MS (M+H)⁺=201.1.

Preparation 92B: 3-Fluoro-4-(4-hydroxypyrimidin-5-yl)picolinonitrile

To a vial charged with 3-fluoro-4-(pyrimidin-5-yl)picolinonitrile (0.400g, 1.998 mmol) in acetone (Volume: 11.89 ml) were added peroxyaceticacid (0.841 ml, 4.00 mmol) and sulfuric acid (0.222 ml, 4.00 mmol). Thereaction mixture was refluxed for 1 h, and then allowed to cool to roomtemperature. The reaction mixture was neutralized with 4 M NaOH andextracted with CH₂Cl₂ (5×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a yellow residue. The crudematerial was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (40 g column, 40 mL/min, 0-25% MeOHin CH₂Cl₂ over 25 min, t_(r)=16 min) gave the title compound (263 mg,1.204 mmol, 60.3% yield) as a yellow solid. ESI MS (M+H)⁺=217.1.

Preparation 92C:(3-Fluoro-4-(4-hydroxypyrimidin-5-yl)pyridin-2-yl)(4-fluorophenyl)methanone

To a solution of 3-fluoro-4-(4-hydroxypyrimidin-5-yl)picolinonitrile(0.152 g, 0.703 mmol) in tetrahydrofuran (Volume: 2.344 ml) cooled to 0°C. was added (4-fluorophenyl)magnesium bromide (1.055 ml, 2.109 mmol).The reaction mixture was allowed to stir at room temperature overnight.Water and ice were carefully added, followed by acidification with 6 MHCl. After stirring for 1 hr, CH₂Cl₂ was added and the pH was adjustedto 8.5 with aqueous 4 M NaOH. The layers were separated. The aqueousphase was extracted with CH₂Cl₂ (5×). Organics combined, dried overNa₂SO₄, filtered, and concentrated to afford an orange residue. Thecrude material was dissolved in a minimal amount of CH₂Cl₂ to bechromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (40 g column, 40 mL/min, 0-20% MeOHin CH₂Cl₂ over 25 min, t_(r)=13 min) gave the title compound (162 mg,0.517 mmol, 73.5% yield) as a yellow residue. ESI MS (M+H)⁺=314.1.

Preparation 92D:(Z)-(3-Fluoro-4-(4-hydroxypyrimidin-5-yl)pyridin-2-yl)(4-fluorophenyl)methanoneoxime

A solution of(3-fluoro-4-(4-hydroxypyrimidin-5-yl)pyridin-2-yl)(4-fluorophenyl)methanone(0.168 g, 0.536 mmol) and hydroxylamine hydrochloride (0.039 g, 0.563mmol) in Pyridine (Volume: 2.68 ml) was refluxed for 1.5 hr, allowed tocool to room temperature, and then concentrated in vacuo. Solvent wasevaporated. The crude material was dissolved in a minimal amount ofCH₂Cl₂ to be chromatographed (required a few drops of MeOH).Purification of the crude material by silica gel chromatography using anISCO machine (24 g column, 35 mL/min, 1-25% MeOH in CH₂Cl₂ over 19 min,t_(r)=12 min) gave the title compound (0.123 g, 0.371 mmol, 69.2% yield)as a tan solid. ESI MS (M+H)⁺=329.1.

Preparation 92E:5-(3-(4-Fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-ol

To a suspension of sodium hydride (0.030 g, 0.742 mmol) in THF (Ratio:1.8, Volume: 2.272 ml) was added dropwise(Z)-(3-fluoro-4-(4-hydroxypyrimidin-5-yl)pyridin-2-yl)(4-fluorophenyl)methanoneoxime (0.116 g, 0.353 mmol) in DMF (Ratio: 1.0, Volume: 1.262 ml)slowly. The reaction mixture was heated at 70° C. for 3.5 hr. AdditionalNaH (12 mg) was added. The reaction mixture was heated at 70° C. for 2.5hr, and then allowed to cool to room temperature. The solvent wasevaporated, and the mixture was further concentrated in vacuo to afforda brown residue. The crude material was dissolved in a minimal amount ofCH₂Cl₂ to be chromatographed (required a few drops of MeOH).Purification of the crude material by silica gel chromatography using anISCO machine (24 g column, 35 mL/min, 0-30% MeOH in CH₂Cl₂ over 25 min,t_(r)=9 min) gave the title compound (53.4 mg, 0.173 mmol, 49.0% yield)as a yellow solid. ESI MS (M+H)⁺=309.1.

Preparation 92F:7-(4-Chloropyrimidin-5-yl)-3-(4-fluorophenyl)isoxazolo[4,5-b]pyridine

A suspension of5-(3-(4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-ol (45 mg,0.146 mmol) in phosphorus oxychloride (503 μl, 5.40 mmol) was heated at90° C. for 1 h, then allowed to cool to room temperature. The solventwas evaporated to afford the title compound (48 mg, 100%).

Example 92

A vial was charged with 4-chloro-5-iodopyrimidine (10 mg, 0.042 mmol)and freshly prepared saturated NH₃/MeOH (0.147 mmol). The reactionmixture was sealed with a Teflon lined screw cap and heated at 90° C.for 2 hr, and then allowed to cool to room temperature. Upon cooling thereaction to room temperature, a solid precipitated and was filtered. Thesolid was washed with MeOH, CH₂Cl₂, CH₃CN, and THF to give the titlecompound (4.7 mg, 10%) as a light brown solid. ESI MS (M+H)⁺=308.1. HPLCPeak t_(r)=1.98 minutes. Purity=98%. HPLC Conditions: C.

Example 937-(4-Methylpyridin-3-yl)-3-(pyridin-2-yl)thieno[3,2-b]pyridine

Preparation 93A: 7-Chlorothieno[3,2-b]pyridine

A suspension of thieno[3,2-b]pyridin-7-ol (4.6 g, 30.4 mmol) in POCl₃(15 mL, 30.4 mmol) was refluxed at 105° C. for 4 hr. The solvent wasevaporated to afford a dark brown oil that was cooled in an ice bath anddiluted with cold water. The aqueous layer was adjusted to a basic pH(˜8) by adding an NH₄OH solution. The aqueous mixture was extracted withEtOAc and DCM. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated to afford an oil. Purificationof the crude material by silica gel chromatography using a BIOTAGE®machine (hexanes:ethyl acetate 75:25) afforded the title compound as apale buff solid (4.7 g, 91%). ESI MS (M+H)⁺=170.0.

Preparation 93B: 7-(4-Methylpyridin-3-yl)thieno[3,2-b]pyridine

A vessel capable of sealing was charged with a mixture of Preparation93A (0.82 g, 4.83 mmol), 4-methylpyridin-3-ylboronic acid (0.993 g, 7.25mmol), Pd(Ph₃P)₄ (279 mg, 0.242 mmol), dioxane (15 mL), and a 2.0 Maqueous solution of K₃PO₄ (7.2 mL, 14.5 mmol) and was purged withnitrogen for 10 min. The vessel was sealed and heated at 90° C. for 16hours. Upon cooling, the reaction mixture was diluted with water andextracted with CH₂Cl₂. The combined organics were washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude material was purified by BIOTAGE® eluting with 30%-100%EtOAc/CH₂Cl₂ at 30 mL/min. Concentration of appropriate fractionsprovided the title compound (540 mg, 49% yield). LC/MS: Example 93B @0.40 min (RT) (Condition G). MS (ES): m/z=227.06 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ ppm 8.81 (1 hr, d, J=4.53 Hz), 8.62 (1 hr, d, J=5.29 Hz),8.57 (1 hr, s), 7.81 (1 hr, d, J=5.54 Hz), 7.68 (1 hr, d, J=5.54 Hz),7.34 (1 hr, d, J=5.04 Hz), 7.18 (1 hr, d, J=4.78 Hz), 2.25 (3 hr, s).

Preparation 93C: 3-Bromo-7-(4-methylpyridin-3-yl)thieno[3,2-b]pyridine

To a stirring solution of Preparation 93B (540 mg, 2.386 mmol) inmethylene chloride (15 mL) was added Br₂ (0.25 mL, 4.77 mmol) inmethylene chloride (2 mL). The reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was quenched withsaturated NaHCO₃ and extracted with CH₂Cl₂. The combined organics werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude material was purified by BIOTAGE® elutingwith 40%-80% EtOAc/CH₂Cl₂ at 30 mL/min. Concentration of appropriatefractions provided the title compound (560 mg, 77% yield). LC/MS:Example 93C @ 1.25 min (RT) (Condition G). MS (ES): m/z=304.92; [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ ppm 8.92 (1 hr, d, J=4.53 Hz), 8.60 (1 hr, d,J=5.04 Hz), 8.52 (1 hr, s), 7.83 (1 hr, s), 7.32 (1 hr, d, J=5.04 Hz),7.25 (1 hr, d, J=4.78 Hz), 2.20 (3 hr, s).

Example 93

A vessel capable of sealing was charged with a mixture of Preparation93C (40 mg, 0.131 mmol), 2-(tributylstannyl)pyridine (72.4 mg, 0.197mmol), Pd(Ph₃P)₄ (7.57 mg, 6.55 μmol), and dioxane (3 mL) and was purgedwith nitrogen for 10 min. The vessel was sealed and heated at 100° C.for 16 hours. Upon cooling, the reaction mixture was concentrated underreduced pressure. The crude material was purified by preparative HPLC.The HPLC fractions that contained the product were concentrated withSPEEDVAC® and applied onto a MCX cartridge. The material was washed withmethanol and the product was eluted with 2N solution of ammonia inmethanol. Concentration provided the title compound as a white powder(27.2 mg, 64.3% yield). LC/MS: Example 93 @ 0.83 min (RT) (Condition G).MS (ES): m/z=304.07 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.05 (1 hr,br. s.), 8.94 (1 hr, d, J=4.78 Hz), 8.78 (1 hr, d, J=5.04 Hz), 8.65 (1hr, d, J=5.04 Hz), 8.60 (1 hr, s), 8.03 (1 hr, br. s.), 7.42 (1 hr, br.s.), 7.37 (1 hr, d, J=5.54 Hz), 7.20-7.32 (2 hr, m), 2.26 (3 hr, s).

Example 947-(4-Methylpyridin-3-yl)-3-(thiazol-2-yl)thieno[3,2-b]pyridine

A vessel capable of sealing was charged with a mixture of Preparation93B (30 mg, 0.098 mmol), 2-(tributylstannyl)thiazole (73.6 mg, 0.197mmol), Pd(Ph₃P)₄ (7.57 mg, 6.55 μmol), and dioxane (3 mL) and was purgedwith nitrogen for 10 min. The vessel was sealed and heated at 100° C.for 16 hours. Upon cooling, the reaction mixture was concentrated underreduced pressure. The crude material was purified by preparative HPLC.The HPLC fractions that contained the product were concentrated withSPEEDVAC® and applied onto a MCX cartridge. The material was washed withmethanol and the product was eluted with 2N solution of ammonia inmethanol. Concentration provided the title compound as a white powder(26.7 mg, 86% yield). LC/MS: Example 94 @ 1.67 min (RT) (Condition G).MS (ES): m/z=310.00 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ ppm 9.02 (1 hr, d,J=4.53 Hz), 8.94 (1 hr, s), 8.85 (1 hr, d, J=6.04 Hz), 8.81 (1 hr, s),8.11 (1 hr, d, J=6.04 Hz), 7.99 (1 hr, d, J=3.27 Hz), 7.76 (1 hr, d,J=3.52 Hz), 7.56 (1 hr, d, J=4.78 Hz), 2.49 (3 hr, s).

Example 957-(4-Methylpyridin-3-yl)-3-(pyrazin-2-yl)thieno[3,2-b]pyridine

A vessel capable of sealing was charged with a mixture of Preparation93B (40 mg, 0.131 mmol), 2-(tributylstannyl)pyrazine (72.6 mg, 0.197mmol), Pd(Ph₃P)₄ (7.57 mg, 6.55 μmol), and dioxane (3 mL) and was purgedwith nitrogen for 10 min. The vessel was sealed and heated at 100° C.for 16 hours. Upon cooling, the reaction mixture was concentrated underreduced pressure. The crude material was purified by preparative HPLC.The HPLC fractions that contained the product were concentrated withSPEEDVAC® and applied onto a MCX cartridge. The material was washed withmethanol and the product was eluted with 2N solution of ammonia inmethanol. Concentration provided the title compound as clear viscous oil(17 mg, 52.3% yield). LC/MS: Example 95 @ 0.1.23 min (RT) (Condition G).MS (ES): m/z=305.07 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ ppm 10.00 (1 hr, d,J=1.51 Hz), 9.04 (1 hr, d, J=4.78 Hz), 8.95 (2 hr, d, J=10.83 Hz), 8.86(1 hr, d, J=5.79 Hz), 8.75 (1 hr, dd, J=2.52, 1.51 Hz), 8.61 (1 hr, d,J=2.52 Hz), 8.10 (1 hr, d, J=6.04 Hz), 7.61 (1 hr, d, J=5.04 Hz), 2.49(3 hr, s).

Example 963-(4-Fluorophenyl)-7-(4-methylpyridin-3-yl)thieno[3,2-b]pyridine

A vessel capable of sealing was charged with a mixture of Preparation93B (40 mg, 0.131 mmol), 4-fluorophenylboronic acid (27.5 mg, 0.197mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (5.4 mg, 6.55 μmol), dioxane (2 mL),and a 2.0 M aqueous solution of K₃PO₄ (0.2 mL, 0.393 mmol) and waspurged with nitrogen for 10 min. The vessel was sealed and heated at 90°C. for 16 hours. Upon cooling, the reaction mixture was diluted withCH₂Cl₂ (10 mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate wasconcentrated under reduced pressure. The crude material was purified bypreparative HPLC. The HPLC fractions that contained the product wereconcentrated with SPEEDVAC® and applied onto a MCX cartridge. Thematerial was washed with methanol and the product was eluted with 2Nsolution of ammonia in methanol. Concentration provided the titlecompound as a white powder (24.9 mg, 58.7% yield). LC/MS: Example 96 @2.20 min (RT) (Condition G). MS (ES): m/z=321.07, [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ ppm 8.91 (1 hr, d, J=4.53 Hz), 8.66 (1 hr, d, J=5.29 Hz),8.62 (1 hr, s), 7.90-8.06 (2 hr, m), 7.84 (1 hr, s), 7.45 (1 hr, t,J=6.30 Hz), 7.13-7.36 (3 hr, m), 2.32 (3 hr, d, J=3.27 Hz).

Example 97 7-(4-Methylpyridin-3-yl)-3-phenylthieno[3,2-b]pyridine

A vessel capable of sealing was charged with a mixture of Preparation93B (30 mg, 0.0.098 mmol), phenylboronic acid (18 mg, 0.147 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (8 mg, 9.8 μmol), dioxane (2 mL), and a 2.0 Maqueous solution of K₃PO₄ (0.15 mL, 0.295 mmol) and was purged withnitrogen for 10 min. The vessel was sealed and heated at 90° C. for 16hours. Upon cooling, the reaction mixture was diluted with CH₂Cl₂ (10mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate was concentratedunder reduced pressure. The crude material was purified by preparativeHPLC. The HPLC fractions that contained the product were concentratedwith SPEEDVAC® and applied onto a MCX cartridge. The material was washedwith methanol and the product was eluted with 2N solution of ammonia inmethanol. Concentration provided the title compound as a white powder(20.1 mg, 67% yield). LC/MS: Example 97 @ 2.08 min (RT) (Condition G).MS (ES): m/z=303.06, [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.95 (1 hr,d, J=4.53 Hz), 8.70 (1 hr, d, J=5.54 Hz), 8.66 (1 hr, s), 7.95-8.06 (2hr, m), 7.90 (1 hr, s), 7.51-7.65 (3 hr, m), 7.38-7.51 (1 hr, m), 7.24(1 hr, d, J=4.53 Hz), 2.41 (3 hr, s).

Example 983-(4-Fluorophenyl)-7-(4-methylpyrimidin-5-yl)thieno[3,2-b]pyridine

Preparation 98A: 7-Chloro-3-(4-fluorophenyl)thieno[3,2-b]pyridine

A vessel capable of sealing was charged with a mixture of3-bromo-7-chlorothieno[3,2-b]pyridine (500 mg, 2.012 mmol),4-fluorophenylboronic acid (310 mg, 2.213 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (82 mg, 0.101 mmol), dioxane (8 mL), and a 2.0 M aqueous solutionof K₃PO₄ (3 mL, 6.04 mmol) and was purged with nitrogen for 10 min. Thevessel was sealed and heated at 90° C. for 1 h. Upon cooling, thereaction mixture was diluted with water and extracted with CH₂Cl₂. Thecombined organics were washed with brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude material was purifiedby BIOTAGE® eluting with 40%-80% EtOAc/CH₂Cl₂ at 30 mL/min.Concentration of appropriate fractions provided the title compound (450mg, 49% yield) as a white powder. LC/MS: Example 98A @ 3.62 min (RT)(Condition G). MS (ES): m/z=263.03, [M+H]⁺.

Example 98

A vessel capable of sealing was charged with a mixture of Preparation98A (65 mg, 0.246 mmol), 4-methylpyrimidin-5-ylboronic acid (51.0 mg,0.370 mmol), Pd(Ph₃P)₄ (14.24 mg, 0.012 mmol), dioxane (4 mL), and a 2.0M aqueous solution of K₃PO₄ (0.4 mL, 0.739 mmol) and was purged withnitrogen for 10 min. The vessel was sealed and heated at 90° C. for 3hours. Upon cooling, the reaction mixture was diluted with CH₂Cl₂ (10mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate was concentratedunder reduced pressure. The crude material was purified by preparativeHPLC. The HPLC fractions that contained the product were concentratedwith SPEEDVAC® and applied onto a MCX cartridge. The material was washedwith methanol and the product was eluted with 2N solution of ammonia inmethanol. Concentration provided the title compound as yellow oil (80mg, 85.1% yield). LC/MS: Example 98 @ 3.19 min (RT) (Condition G). MS(ES): m/z=322.08, [M+H]⁺. ¹H NRM (400 MHz, MeOD) δ ppm 9.21 (1 hr, s),8.88 (1 hr, d, J=5.02 Hz), 8.79 (1 hr, s), 8.18 (1 hr, s), 7.98 (2 hr,dd, J=9.03, 5.52 Hz), 7.51 (1 hr, d, J=4.77 Hz), 7.25 (2 hr, t, J=8.91Hz), 2.48 (3 hr, s).

Example 997-(4-Cyclopropylpyrimidin-5-yl)-3-(4-fluorophenyl)thieno[3,2-b]pyridine

Preparation 99A: 4-Cyclopropylpyrimidin-5-ylboronic acid

A vessel capable of sealing was charged with a mixture of Preparation11A (140 mg, 0.703 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (268 mg,1.055 mmol), potassium acetate (207 mg, 2.110 mmol),PdCl₂(dppf)-CH₂Cl₂adduct (28.7 mg, 0.035 mmol), and dioxane (6 mL) andwas purged with nitrogen for 10 min. The vessel was sealed and heated to90° C. for 3 hours. Upon cooling, the reaction mixture was diluted withEtOAc (20 mL) and filtered with EtOAc. The filtrate was concentratedunder reduced pressure. LC/MS: Example 99A @ 0.52 min (RT) (ConditionG). MS (ES): m/z=164.17, [M+H]⁺.

Example 99

A vessel capable of sealing was charged with a mixture of Preparation98A (65 mg, 0.246 mmol), Preparation 99A (60.6 mg, 0.370 mmol),Pd(Ph₃P)₄ (14.24 mg, 0.012 mmol), dioxane (4 mL), and a 2.0 M aqueoussolution of K₃PO₄ (0.4 mL, 0.739 mmol) and was purged with nitrogen for10 min. The vessel was sealed and heated at 90° C. for 3 hours. Uponcooling, the reaction mixture was diluted with CH₂Cl₂ (10 mL) andfiltered with CH₂Cl₂/MeOH washing. The filtrate was concentrated underreduced pressure. The crude material was purified by preparative HPLC.The HPLC fractions that contained the product were concentrated withSPEEDVAC® and applied onto a MCX cartridge. The material was washed withmethanol and the product was eluted with 2N solution of ammonia inmethanol. Concentration provided the title compound as a white solid(50.8 mg, 44.5% yield). HPLC/MS: Example 99 @ 3.57 min (RT) (ConditionG). MS (ES): m/z=348.09, [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ ppm 9.09 (1hr, s), 8.88 (1 hr, d, J=4.77 Hz), 8.65 (1 hr, s), 8.15 (1 hr, s),7.93-8.08 (2 hr, m), 7.52 (1 hr, d, J=4.77 Hz), 7.16-7.39 (2 hr, m),1.74-1.98 (1 hr, m), 1.35 (2 hr, quin, J=3.70 Hz), 0.99-1.22 (2 hr, m).

Example 1005-(3-(4-Fluorophenyl)thieno[3,2-b]pyridin-7-yl)pyrimidin-4-amine

A vessel capable of sealing was charged with a mixture of Preparation98A (120 mg, 0.455 mmol), 4-aminopyrimidin-5-ylboronic acid (126 mg,0.910 mmol), Pd(Ph₃P)₄ (26.3 mg, 0.023 mmol), dioxane (10 mL), and a 2.0M aqueous solution of K₃PO₄ (0.68 mL, 1.365 mmol) and was purged withnitrogen for 10 min. The vessel was sealed and heated at 90° C. for 6hours. Upon cooling, the reaction mixture was diluted with CH₂Cl₂ (10mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate was concentratedunder reduced pressure. The crude material was purified by preparativeHPLC. The HPLC fractions that contained the product were concentratedwith SPEEDVAC® and applied onto a MCX cartridge. The material was washedwith methanol and the product was eluted with 2N solution of ammonia inmethanol. Concentration provided the title compound as a white powder(45 mg, 30.7% yield). LC/MS: Example 100 @ 2.13 min (RT) (Condition G).MS (ES): m/z=357.08, [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ ppm 8.90 (1 hr, d,J=4.77 Hz), 8.80 (1 hr, d, J=1.51 Hz), 8.47 (1 hr, d, J=1.25 Hz), 8.20(1 hr, s), 8.04 (2 hr, dd, J=8.91, 5.40 Hz), 7.54 (1 hr, d, J=4.77 Hz),7.26 (2 hr, t, J=8.91 Hz).

Example 1015-(3-(4-Fluoro-2-(trifluoromethyl)phenyl)thieno[3,2-b]pyridin-7-yl)pyrimidin-4-amine

Preparation 101A:7-Chloro-3-(4-fluoro-2-(trifluoromethyl)phenyl)thieno[3,2-b]pyridine

A vessel capable of sealing was charged with a mixture of3-bromo-7-chlorothieno[3,2-b]pyridine (123 mg, 0.495 mmol),4-fluoro-2-(trifluoromethyl) phenylboronic acid (123 mg, 0.594 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (20.21 mg, 0.0.025 mmol), dioxane (6 mL), anda 2.0 M aqueous solution of K₃PO₄ (0.74 mL, 1.485 mmol) and was purgedwith nitrogen for 10 min. The vessel was sealed and heated at 90° C. for3 hours. Upon cooling, the reaction mixture was diluted with CH₂Cl₂ andfiltered with CH₂Cl₂/MeOH washing. The filtrate was concentrated underreduced pressure. The residue was dissolved in CH₂Cl₂ and washed withwater, brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude material was purified by BIOTAGE® eluting with40%-60% CH₂Cl₂/hexanes at 30 mL/min. Concentration of appropriatefractions provided the title compound (150 mg, 91% yield) as a whitesolid. LC/MS: Example 101A @ 3.94 min (RT) (Condition G). MS (ES):m/z=331.94, [M+H]⁺.

Example 101

A vessel capable of sealing was charged with a mixture of Preparation101A (80 mg, 0.241 mmol), 4-aminopyrimidin-5-ylboronic acid (67.0 mg,0.482 mmol), Pd(Ph₃P)₄ (13.9 mg, 0.012 mmol), dioxane (4 mL), and a 2.0M aqueous solution of K₃PO₄ (0.36 mL, 0.724 mmol) and was purged withnitrogen for 10 min. The vessel was sealed and heated at 90° C. for 6hours. Upon cooling, the reaction mixture was diluted with CH₂Cl₂ (10mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate was concentratedunder reduced pressure. The crude material was purified by preparativeHPLC. The HPLC fractions that contained the product were concentratedwith SPEEDVAC® and applied onto a MCX cartridge. The material was washedwith methanol and the product was eluted with 2N solution of ammonia inmethanol. Concentration provided the title compound as a white powder(20.8 mg, 21.6% yield). LC/MS: Example 101 @ 2.13 min (RT) (ConditionG). MS (ES): m/z=357.08, [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ ppm 8.96 (1hr, d, J=4.77 Hz), 8.81 (1 hr, d, J=1.51 Hz), 8.53 (1 hr, dd, J=6.78,2.01 Hz), 8.48 (1 hr, d, J=1.51 Hz), 8.39 (1 hr, s), 8.21-8.38 (1 hr,m), 7.57 (1 hr, d, J=4.77 Hz), 7.40-7.54 (1 hr, m).

Example 1025-(3-(2,4-Difluorophenyl)thieno[3,2-b]pyridin-7-yl)pyrimidin-4-amine

Preparation 102A: 7-Chloro-3-(2,4-difluorophenyl)thieno[3,2-b]pyridine

A vessel capable of sealing was charged with a mixture of3-bromo-7-chlorothieno[3,2-b]pyridine (110 mg, 0.443 mmol),2,4-difluorophenylboronic acid (84 mg, 0.531 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (18.1 mg, 0.022 mmol), dioxane (3 mL), and a 2.0 M aqueoussolution of K₃PO₄ (0.66 mL, 1.328 mmol) and was purged with nitrogen for10 min. The vessel was sealed and heated at 90° C. for 3 hours. Uponcooling, the reaction mixture was diluted with water and extracted withCH₂Cl₂. The combined organics were washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudematerial was purified by BIOTAGE® eluting with 30%-60% CH₂Cl₂/hexanes at30 mL/min. Concentration of appropriate fractions provided the titlecompound (450 mg, 49% yield) as a white powder. LC/MS: Example 102A @3.60 min (RT) (Condition G). MS (ES): m/z=282.02/284.02, [M+H]⁺.

Example 102

A vessel capable of sealing was charged with a mixture of Preparation102A (90 mg, 0.319 mmol), 4-aminopyrimidin-5-ylboronic acid (89 mg,0.639 mmol), Pd(Ph₃P)₄ (18.5 mg, 0.016 mmol), dioxane (6 mL), and a 2.0M aqueous solution of K₃PO₄ (0.48 mL, 0.958 mmol) and was purged withnitrogen for 10 min. The vessel was sealed and heated at 90° C. for 6hours. Upon cooling, the reaction mixture was diluted with CH₂Cl₂ (10mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate was concentratedunder reduced pressure. The crude material was purified by preparativeHPLC. The HPLC fractions that contained the product were concentratedwith SPEEDVAC® and applied onto a MCX cartridge. The material was washedwith methanol and the product was eluted with 2N solution of ammonia inmethanol. Concentration provided the title compound as a white powder(6.6 mg, 5.8% yield). LC/MS: Example 102 @ 2.25 min (RT) (Condition G).MS (ES): m/z=341.08, [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ ppm 8.87 (1 hr, d,J=4.77 Hz), 8.81 (1 hr, d, J=1.51 Hz), 8.48 (1 hr, d, J=1.26 Hz), 8.24(1 hr, d, J=1.00 Hz), 7.93 (1 hr, td, J=8.66, 6.53 Hz), 7.56 (1 hr, d,J=4.77 Hz), 7.08-7.24 (2 hr, m).

Example 1035-(3-(2-Chloro-4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)pyrimidin-4-amine

Preparation 103A:7-Chloro-3-(2-chloro-4-fluorophenyl)thieno[3,2-b]pyridine

A vessel capable of sealing was charged with a mixture of3-bromo-7-chlorothieno[3,2-b]pyridine (260 mg, 1.046 mmol),2-chloro-4-fluorophenylboronic acid (274 mg, 1.569 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (42.7 mg, 0.0.052 mmol), dioxane (8 mL), and a2.0 M aqueous solution of K₃PO₄ (1.6 mL, 3.14 mmol) and was purged withnitrogen for 10 min. The vessel was sealed and heated at 90° C. for 3 h.Upon cooling, the reaction mixture was diluted with water and extractedwith CH₂Cl₂. The combined organics were washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudematerial was purified by BIOTAGE® eluting with 60%-100% CH₂Cl₂/hexanesat 30 mL/min. Concentration of appropriate fractions provided the titlecompound (250 mg, 80% yield) as a white solid. LC/MS: Example 103A @3.58 min (RT) (Condition G). MS (ES): m/z=297.89, [M+H]+.

Preparation 103B:3-(2-Chloro-4-fluorophenyl)-7-iodothieno[3,2-b]pyridine

A mixture of Preparation 103A (180 mg, 0.604 mmol) and HI (5 mL, 47%water solution, excess) was heated at 100° C. overnight. The reactionmixture was cooled to room temperature, carefully quenched with NaHCO₃,and extracted with CH₂Cl₂. The combined organics were washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude material was used for the next step without purification. LC/MS:Example 103B @ 3.04 min (RT) (Condition G). MS (ES): m/z=298.01, [M+H]⁺.

Example 103

A vessel capable of sealing was charged with a mixture of Preparation103B (130 mg, 0.334 mmol), 4-aminopyrimidin-5-ylboronic acid (69.5 mg,0.500 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (13.62 mg, 0.017 mmol), dioxane(2 mL), and a 2.0 M aqueous solution of K₃PO₄ (0.5 mL, 1.00 mmol) andwas purged with nitrogen for 10 min. The vessel was sealed and heated at80° C. for 2 hours. Upon cooling, the reaction mixture was diluted withCH₂Cl₂ (10 mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate wasconcentrated under reduced pressure. The crude material was purified bypreparative HPLC. The HPLC fractions that contained the product wereconcentrated with SPEEDVAC® and applied onto a MCX cartridge. Thematerial was washed with methanol and the product was eluted with 2Nsolution of ammonia in methanol. Concentration provided the titlecompound as a white powder (50.8 mg, 44.5% yield). LC/MS: Example 103 @2.13 min (RT) (Condition G). MS (ES): m/z=357.08, [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.75 (1 hr, d, J=4.77 Hz), 8.52 (1 hr, s), 8.29 (2hr, d, J=17.07 Hz), 7.65 (2 hr, dd, J=8.41, 2.13 Hz), 7.46 (1 hr, d,J=4.77 Hz), 7.39 (1 hr, td, J=8.53, 2.76 Hz).

Example 104N-(3-Amino-7-(4-methylpyridin-3-yl)benzo[d]isoxazol-4-yl)methanesulfonamide

Preparation 104A: 6-Amino-2-fluoro-3-iodobenzonitrile

To a solution of 2-amino-6-fluorobenzonitrile (3 g, 0.022 mol) in CH₂Cl₂(200 mL) and MeOH (50 mL) was added sodium bicarbonate (3.7 g, 0.044mmol) and ICl (3.75 g, 0.023 mol) in CH₂Cl₂ (20 mL). The suspension wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated and the residue was partitioned between CH₂Cl₂ and water.The organic layer was washed with Na₂S₂O₃, water, and brine. The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude material was triturated with ether. Filtration gave the titlecompound as a brown solid (2.5 g, 43% yield). LC/MS: Example 104A @ 2.86min (RT) (Condition G). MS (ES): m/z=262.93, [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.60 (1 hr, dd, J=8.78, 7.03 Hz), 6.39 (1 hr, d, J=8 Hz).

Preparation 104B: N-(2-Cyano-3-fluoro-4-iodophenyl)methanesulfonamide

To a solution of Preparation 104A (2.2 g, 8.40 mmol) in pyridine (15 mL)was added methanesulfonyl chloride (1.010 g, 8.82 mmol). The reactionmixture was heated at 80° C. for 5 hours. After 5 hours, methanesulfonylchloride (200 mg) was added to the reaction mixture. The reactionmixture was heated at 80° C. for another 2 hours. Upon cooling, thereaction mixture was diluted with water and extracted with CH₂Cl₂. Thecombined organics were washed with brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude material was purifiedby BIOTAGE® eluting with 10%-50% EtOAc/CH₂Cl₂ at 30 mL/min.Concentration of appropriate fractions provided the title compound (830mg, 29% yield) as a white powder. LC/MS: Example 104B @ 2.44 min (RT)(Condition G). MS (ES): m/z=340.92, [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ ppm8.08 (1 hr, dd, J=8.78, 7.03 Hz), 7.26 (1 hr, dd, J=8.78, 1.00 Hz), 3.16(3 hr, s).

Preparation 104C:N-(3-Amino-7-iodobenzo[d]isoxazol-4-yl)methanesulfonamide

To a solution of Preparation 104B (800 mg, 2.352 mmol) in DMF/water(1:1, 14 mL) were added N-hydroxyacetamide (706 mg, 9.41 mmol) andpotassium carbonate (1.63 g, 11.76 mmol). The reaction mixture washeated to 80° C. overnight. Upon cooling, the reaction mixture wasdiluted with water (30 mL) and extracted with 20% MeOH/CHCl₃. Thecombined organics were washed with brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude material was purifiedby BIOTAGE® eluting with 10%-40% EtOAc/CH₂Cl₂ at 30 mL/min.Concentration of appropriate fractions provided the title compound (350mg, 42.1% yield) as a white solid. LC/MS: Example 104C @ 2.18 min (RT)(Condition G). MS (ES): m/z=353.95, [M+H]⁺.

Example 104

A vessel capable of sealing was charged with a mixture of Preparation104C 2 TFA (36 mg, 0.062 mmol), 4-methylpyridin-3-ylboronic acid (16.97mg, 0.124 mmol), mmol), Pd(Ph₃P)₄ (7.16 mg, 6.19 μmol), dioxane (2 mL),and a 2.0 M aqueous solution of K₃PO₄ (0.12 mL, 0.310 mmol) and waspurged with nitrogen for 10 min. The vessel was sealed and heated at 80°C. for 12 hours. Upon cooling, the reaction mixture was diluted withCH₂Cl₂ (10 mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate wasconcentrated under reduced pressure. The crude material was purified bypreparative HPLC. The HPLC fractions that contained the product wereconcentrated with SPEEDVAC® and applied onto a MCX. The material waswashed with methanol and the product was eluted with 2N solution ofammonia in methanol. Concentration provided the title compound as awhite powder (10.6 mg, 51.6% yield). LC/MS: Example 104 @ 3.32 min (RT)(Condition G). MS (ES): m/z=355.98 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ ppm8.85 (1 hr, s), 8.77 (1 hr, d, J=6.02 Hz), 8.06 (1 hr, d, J=6.02 Hz),7.67 (1 hr, d, J=8.03 Hz), 7.43 (1 hr, d, J=7.78 Hz), 3.15 (3 hr, s).

Example 105N-(7-(4-Methylpyridin-3-yl)benzo[b]thiophen-4-yl)methanesulfonamide

Preparation 105A: N-(Benzo[b]thiophen-4-yl)methanesulfonamide

To a stirred solution of benzo[b]thiophen-4-amine (1 g, 6.70 mmol) andpyridine (1.355 mL, 16.75 mmol) in CH₂Cl₂ (15 mL) was added dropwisemethanesulfonyl chloride (0.574 mL, 7.37 mmol) at 0° C. under nitrogenatmosphere. The reaction mixture was then allowed to warm to roomtemperature while stirring overnight. The reaction mixture was washedwith saturated sodium bicarbonate solution, water, brine and dried oversodium sulfate. Evaporation of the solvent furnished a crude residue,which was subjected to BIOTAGE® (100% methylene chloride) to give thetitle compound as a white solid (1.2 g, 79%). LC/MS: Example 105A @ 2.88min (RT) (Condition H). MS (ES): m/z=226.0, [M+H]⁺. ¹H NMR (400 MHz,MeOD) δ ppm 7.77 (1 hr, d, J=7.81 Hz), 7.59 (2 hr, d, J=1.26 Hz),7.25-7.42 (2 hr, m), 2.94 (3 hr, s).

Preparation 105B: N-(7-Iodobenzo[b]thiophen-4-yl)methanesulfonamide

To a stirred solution of Preparation 105A (1.13 g, 4.97 mmol) inpyridine (10 mL) was added iodine (1.514 g, 5.97 mmol), and the mixturewas stirred at room temperature for 14 h. The reaction mixture wasdiluted with ether, washed with saturated sodium thiosulfate solution,water, brine and dried. Evaporation of the solvent furnished a cruderesidue, which was chromatographed (100% CH₂Cl₂) to furnish the titlecompound, which was used without further purification. LC/MS: Example105B @ 3.47 min (RT) (Condition H). MS (ES): m/z=352.0, [M−H]⁺.

Example 105

A vessel capable of sealing was charged with a mixture of Preparation105B (300 mg, 0.849 mmol), 4-methylpyridin-3-ylboronic acid (157 mg,1.274 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (69.4 mg, 0.085 mmol), dioxane (4mL), and a 2.0 M aqueous solution of K₃PO₄ (1.3 mL, 2.55 mmol) and waspurged with nitrogen for 10 min. The vessel was sealed and heated at 90°C. for 16 hours. Upon cooling, the solvent was evaporated to dryness andthe residue was suspended in ethyl acetate, washed with water, brine anddried over sodium sulfate. Evaporation of the solvent furnished a cruderesidue, which was chromatographed using BIOTAGE® (20% EtOAc/CH₂Cl₂).Concentration provided the title compound as a white powder (60 mg, 22%yield). LC/MS: Example 105 @ 3.12 min (RT) (Condition H). MS (ES):m/z=317.1, [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ ppm 8.46 (1 hr, d, J=5.29Hz), 8.39 (1 hr, s), 7.71 (1 hr, d, J=5.79 Hz), 7.63 (1 hr, d, J=5.79Hz), 7.54 (1 hr, d, J=7.81 Hz), 7.44 (1 hr, d, J=5.29 Hz), 7.25 (1 hr,d, J=7.81 Hz), 3.03 (3 hr, s), 2.19 (3 hr, s).

Example 106N-(7-(4-Cyclopropylpyrimidin-5-yl)benzo[b]thiophen-4-yl)methanesulfonamide

A vessel capable of sealing was charged with a mixture of Preparation105B (287 mg, 0.813 mmol), Preparation 99A (200 mg, 1.220 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (66.4 mg, 0.81 mmol), dioxane (6 mL), and a2.0 M aqueous solution of K₃PO₄ (1.2 mL, 2.439 mmol) and was purged withnitrogen for 10 min. The vessel was sealed and heated at 90° C. for 2hours. Upon cooling, the reaction mixture was diluted with CH₂Cl₂ (10mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate was concentratedunder reduced pressure. The crude material was purified by preparativeHPLC. The HPLC fractions that contained the product were concentratedwith SPEEDVAC® and applied onto a MCX cartridge. The material was washedwith methanol and the product was eluted with 2N solution of ammonia inmethanol. Concentration provided the title compound as an off whitesolid (45 mg, 16% yield). LC/MS: Example 106 @ 3.3 min (RT) (ConditionH). MS (ES): m/z=344.2/391.91, [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ ppm9.00-9.09 (1 hr, m), 8.53-8.65 (1 hr, m), 7.76 (1 hr, t, J=6.10 Hz),7.69 (1 hr, t, J=5.80 Hz), 7.61 (1 hr, t, J=7.17 Hz), 7.35-7.51 (1 hr,m), 2.99-3.11 (3 hr, m), 1.79-1.93 (1 hr, m), 1.30 (2 hr, br. s.),0.94-1.12 (2 hr, m).

Example 107N-(7-(4-Cyclopropylpyridin-3-yl)benzo[b]thiophen-4-yl)methanesulfonamide

A microwave vial was charged with a mixture of4-cyclopropylpyridin-3-ylboronic acid (180 mg, 1.104 mmol), Preparation105B (260 mg, 0.736 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (60.1 mg, 0.074mmol), dioxane (6 mL), and a 2.0 M aqueous solution of K₃PO₄ (1.1 mL,2.209 mmol) and was purged with nitrogen for 10 min. The vial was sealedand heated at 90° C. for 2 hours in the microwave. Upon cooling, thereaction mixture was diluted with CH₂Cl₂ (10 mL) and filtered withCH₂Cl₂/MeOH washing. The filtrate was concentrated under reducedpressure. The crude material was purified by preparative HPLC. The HPLCfractions that contained the product were concentrated with SPEEDVAC®and applied onto a MCX cartridge. The material was washed with methanoland the product was eluted with 2N solution of ammonia in methanol.Concentration provided the title compound as an off white solid (45 mg,16% yield). LC/MS: Example 107 @ 3.31 min (RT) (Condition H). MS (ES):m/z=345.2, [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ ppm 8.74 (1 hr, d, J=11.29Hz), 8.71 (1 hr, br. s.), 7.77-7.85 (1 hr, m), 7.73 (1 hr, d, J=5.49Hz), 7.66 (1 hr, d, J=7.63 Hz), 7.58 (1 hr, d, J=6.41 Hz), 7.48 (1 hr,d, J=7.93 Hz), 3.10 (3 hr, s), 1.81-2.01 (1 hr, m), 1.33 (2 hr, br. s.),1.24 (2 hr, br. s.).

Example 1085-(3-(4-Fluorophenyl)benzo[b]thiophen-7-yl)-4-methylpyrimidine

Preparation 108A: 5-(Benzo[b]thiophen-7-yl)-4-methylpyrimidine

A vessel capable of sealing was charged with a mixture of7-bromobenzo[b]thiophene (100 mg, 0.467 mmol),4-methylpyrimidin-5-ylboronic acid (97 mg, 0.70 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (19.2 mg, 0.023 mmol), dioxane (3 mL), and a2.0 M water solution of K₃PO₄ (0.7 mL, 1.41 mmol) and was purged withnitrogen for 10 min. The vessel was sealed and heated at 100° C. for 16hours. Upon cooling, the reaction mixture was diluted with CH₂Cl₂ andfiltered with CH₂Cl₂/MeOH washing. The filtrate was concentrated underreduced pressure. The residue was dissolved in CH₂Cl₂ and washed withwater, brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude material was purified by BIOTAGE® eluting with0%-15% EtOAc/CH₂Cl₂ at 30 mL/min. Concentration of appropriate fractionsprovided the title compound (32 mg, 30% yield). LC/MS: Example 108A @2.49 min (RT) (Condition G). MS (ES): m/z=227.07.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ ppm 9.19 (1 hr, s), 8.68 (1 hr, s), 7.92 (1 hr, d, J=8.06Hz), 7.38-7.52 (3 hr, m), 7.23 (1 hr, d, J=7.05 Hz), 2.44 (3 hr, s).

Preparation 108B: 5-(3-Bromobenzo[b]thiophen-7-yl)-4-methylpyrimidine

To a stirring solution of Preparation 108B (32 mg, 0.141 mmol) inmethylene chloride (5 mL) was added Br₂ (45.2 mg, 0.283 mmol) inmethylene chloride (2 mL). The reaction mixture was stirred at roomtemperature for 2 hours. The reaction was quenched with saturatedNaHCO₃. The reaction mixture and extracted with CH₂Cl₂. The combinedorganics were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude material was used fornext step without purification. LC/MS: Example 108B @ 3.04 min (RT)(Condition G). MS (ES): m/z=304.89; [M+H]⁺.

Example 108

A vessel capable of sealing was charged with a mixture of Preparation108B (30 mg, 0.098 mmol), 4-fluorophenylboronic acid (20.63 mg, 0.147mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (8.03 mg, 9.83 μmol), dioxane (2 mL),and a 2.0 M aqueous solution of K₃PO₄ (0.15 mL, 0.295 mmol) and waspurged with nitrogen for 10 min. The vessel was sealed and heated at 90°C. for 16 hours. Upon cooling, the reaction mixture was diluted withCH₂Cl₂ (10 mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate wasconcentrated under reduced pressure. The crude material was purified bypreparative HPLC. The HPLC fractions that contained the product wereconcentrated with SPEEDVAC® and applied onto a MCX cartridge. Thematerial was washed with methanol and the product was eluted with 2Nsolution of ammonia in methanol. Concentration provided the titlecompound as brown oil (2.9 mg, 6.2% yield). LC/MS: Example 108 @ 3.34min (RT) (Condition G). MS (ES): m/z=321.01 [M+H]⁺. ¹H NMR (400 MHz,MeOD) δ ppm 9.12 (1 hr, s), 8.69 (1 hr, s), 7.90-8.01 (1 hr, m),7.57-7.69 (5 hr, m), 7.36 (1 hr, d, J=7.05 Hz), 7.25 (2 hr, t, J=8.81Hz), 2.40 (3 hr, s).

Example 109 4-(3-(4-Fluorophenyl)benzo[b]thiophen-7-yl)isoquinoline

Preparation 109A: 4-(Benzo[b]thiophen-7-yl)isoquinoline

A vessel capable of sealing was charged with a mixture of7-bromobenzo[b]thiophene (430 mg, 2.018 mmol), isoquinolin-4-ylboronicacid (419 mg, 2.421 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (82 mg, 0.101mmol), dioxane (6 mL), and a 2.0 M aqueous solution of K₃PO₄ (3 mL, 1.41mmol) and was purged with nitrogen for 10 min. The vessel was sealed andheated at 90° C. for 16 hours. Upon cooling, the reaction mixture wasdiluted with CH₂Cl₂ and filtered with CH₂Cl₂/MeOH washing. The filtratewas concentrated under reduced pressure. The residue was dissolved inCH₂Cl₂ and washed with water, brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude material was purified byBIOTAGE® eluting with 0%-15% EtOAc/CH₂Cl₂ at 30 mL/min. Concentration ofappropriate fractions provided the title compound (32 mg, 30% yield).LC/MS: Example 109A @ 2.49 min (RT) (Condition G). MS (ES): m/z=262.42[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.38 (1 hr, s), 8.71 (1 hr, s),8.08-8.15 (1 hr, m), 7.96 (1 hr, dd, J=8.06, 1.01 Hz), 7.51-7.71 (4 hr,m), 7.39-7.51 (3 hr, m).

Preparation 109B: 4-(3-Bromobenzo[b]thiophen-7-yl)isoquinoline

To a stirring solution of Preparation 109A (150 mg, 0.574 mmol) inmethylene chloride (10 mL) was added Br₂ (183 mg, 1.148 mmol) inmethylene chloride (2 mL). The reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was quenched withsaturated NaHCO₃ and extracted with CH₂Cl₂. The combined organics werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude material was purified by BIOTAGE® elutingwith 0%-10% EtOAc/CH₂Cl₂ at 30 mL/min. Concentration of appropriatefractions provided the title compound (86 mg, 44% yield). LC/MS: Example109B @ 3.06 min (RT) (Condition G). MS (ES): m/z=339.90; [M+H]⁺.

Example 109

A vessel capable of sealing was charged with a mixture of Preparation109B (40 mg, 0.118 mmol), 4-fluorophenylboronic acid (19.74 mg, 0.141mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (4.8 mg, 5.88 μmol), dioxane (2 mL),and a 2.0 M aqueous solution of K₃PO₄ (0.18 mL, 0.353 mmol) and waspurged with nitrogen for 10 min. The vessel was sealed and heated at 90°C. for 16 hours. Upon cooling, the reaction mixture was diluted withCH₂Cl₂ (10 mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate wasconcentrated under reduced pressure. The crude material was purified bypreparative HPLC. The HPLC fractions that contained the product wereconcentrated with SPEEDVAC® and applied onto a MCX cartridge. Thematerial was washed with methanol and the product was eluted with 2Nsolution of ammonia in methanol. Concentration provided the titlecompound as a white powder (16.5 mg, 39.1% yield). LC/MS: Example 109 @3.32 min (RT) (Condition G). MS (ES): m/z=355.98 [M+H]⁺. ¹H NMR (400MHz, MeOD) δ ppm 8.78 (1 hr, s), 8.64 (1 hr, d, J=8.24 Hz), 8.04-8.21 (3hr, m), 7.90 (1 hr, d, J=8.24 Hz), 7.56-7.75 (5 hr, m), 7.22-7.38 (2 hr,m).

Example 1104-(3-(2-Chloro-4-fluorophenyl)benzo[b]thiophen-7-yl)isoquinoline

A vessel capable of sealing was charged with a mixture of Preparation109B (40 mg, 0.118 mmol), 2-chloro-4-fluorophenylboronic acid (24.60 mg,0.141 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (4.8 mg, 5.88 μmol), dioxane (2mL), and a 2.0 M aqueous solution of K₃PO₄ (0.18 mL, 0.353 mmol) and waspurged with nitrogen for 10 min. The vessel was sealed and heated at 90°C. for 16 hours. Upon cooling, the reaction mixture was diluted withCH₂Cl₂ (10 mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate wasconcentrated under reduced pressure. The crude material was purified bypreparative HPLC. The HPLC fractions that contained the product wereconcentrated with SPEEDVAC® and applied onto a MCX cartridge. Thematerial was washed with methanol and the product was eluted with 2Nsolution of ammonia in methanol. Concentration provided the titlecompound as a gray powder (18.3 mg, 36.7% yield). LC/MS: Example 110 @3.42 min (RT) (Condition G). MS (ES): m/z=389.91, [M+H]⁺. ¹H NMR (400MHz, MeOD) δ ppm 9.90 (1 hr, s), 8.80 (1 hr, s), 8.66 (1 hr, d, J=8.24Hz), 8.06-8.24 (2 hr, m), 7.93 (1 hr, d, J=8.24 Hz), 7.44-7.77 (6 hr,m), 7.28 (1 hr, td, J=8.32, 2.59 Hz).

Example 111 3-(3-(4-Fluorophenyl)benzo[b]thiophen-7-yl)-4-methylpyridine

Preparation 111A: 3-(Benzo[b]thiophen-7-yl)-4-methylpyridine

A vessel capable of sealing was charged with a mixture of7-bromobenzo[b]thiophene (370 mg, 1.736 mmol),4-methylpyridin-3-ylboronic acid HCl (361 mg, 2.084 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (70.9 mg, 0.087 mmol), dioxane (8 mL), and a2.0 M aqueous solution of K₃PO₄ (3.47 mL, 6.95 mmol) and was purged withnitrogen for 10 min. The vessel was sealed and heated at 90° C. for 10hours. Upon cooling, the reaction mixture was diluted with CH₂Cl₂ andfiltered with CH₂Cl₂/MeOH washing. The filtrate was concentrated underreduced pressure. The residue was dissolved in CH₂Cl₂ and washed withwater, brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude material was purified by BIOTAGE® eluting with10%-40% EtOAc/CH₂Cl₂ at 30 mL/min. Concentration of appropriatefractions provided the title compound (350 mg, 89% yield). LC/MS:Example 111A @ 1.50 min (RT) (Condition G). MS (ES): m/z=226.12.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.50-8.64 (2 hr, m), 7.89 (1 hr,dd, J=7.93, 1.13 Hz), 7.40-7.55 (3 hr, m), 7.25-7.33 (1 hr, m), 7.22 (1hr, d, J=6.30 Hz), 2.21 (3 hr, s).

Preparation 111B: 3-(3-Bromobenzo[b]thiophen-7-yl)-4-methylpyridine

To a stirring solution of Preparation 111A (70 mg, 0.311 mmol) inmethylene chloride (10 mL) was added Br₂ (0.016 mL, 0.311 mmol) inmethylene chloride (0.4 mL). The reaction mixture was stirred at roomtemperature for 30 min. The reaction was quenched with saturated NaHCO₃and extracted with CH₂Cl₂. The combined organics were washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude material was purified by BIOTAGE® eluting with 10%-40%EtOAc/CH₂Cl₂ at 30 mL/min. Concentration of appropriate fractionsprovided the title compound as brown oil (73 mg, 83% yield). LC/MS:Example 111B @ 2.20 min (RT) (Condition G). MS (ES): m/z=303.94; [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ ppm 8.58 (1 hr, d, J=5.04 Hz), 8.54 (1 hr, s),7.87-7.98 (1 hr, m), 7.55-7.66 (1 hr, m), 7.49 (1 hr, s), 7.25-7.36 (2hr, m), 2.19 (3 hr, s).

Example 111

A vessel capable of sealing was charged with a mixture of Preparation111B (40 mg, 0.131 mmol), 4-fluorophenylboronic acid (27.6 mg, 0.197mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (5.37 mg, 6.57 μmol), dioxane (3 mL),and a 2.0 M aqueous solution of K₃PO₄ l (0.2 mL, 0.394 mmol) and waspurged with nitrogen for 10 min. The vessel was sealed and heated at 90°C. for 16 hours. Upon cooling, the reaction mixture was diluted withCH₂Cl₂ (10 mL) and filtered with CH₂Cl₂/MeOH washing. The filtrate wasconcentrated under reduced pressure. The crude material was purified bypreparative HPLC. The HPLC fractions that contained the product wereconcentrated with SPEEDVAC® and applied onto a MCX cartridge. Thematerial was washed with methanol and the product was eluted with 2Nsolution of ammonia in methanol. Concentration provided the titlecompound as clear viscous oil (21.4 mg, 49% yield). LC/MS: Example 111 @2.64 min (RT) (Condition G). MS (ES): m/z=320.07 [M+H]⁺. ¹H NMR (400MHz, MeOD) δ ppm 8.82 (1 hr, s), 8.78 (1 hr, d, J=6.04 Hz), 8.06 (1 hr,d, J=5.79 Hz), 8.00 (1 hr, d, J=8.06 Hz), 7.52-7.72 (4 hr, m), 7.42 (1hr, d, J=7.05 Hz), 7.25 (2 hr, t, J=8.69 Hz), 2.46 (3 hr, s).

Examples 112 to 114

The following compounds were synthesized from Example 50 and a varietyof alcohols using the following procedure:

TABLE 1

LC/MS* Ex. R Compound Name ret. T (min.) [M + H]⁺ 112

4-methyl-3-(3-(pyridin-2-yl)benzo [b]thiophen-7-yl)pyridine 1.15 303.00113

3-(3-(2,4-difluorophenyl)benzo[b] thiophen-7-yl)-4-methylpyridine 2.63338.02 114

3-(3-(2-chloro-4-fluorophenyl) benzo[b]thiophen-7-yl)-4- methylpyridine2.80 353.97 *LC/MS retention times for Compounds 112-114 were obtainedusing HPLC condition G: PHENOMENEX®-Luna 4.6 x 30 mm S10, 4 minutegradient time, flow rate: 4.0 mL/min, Solvent A: 10% MeOH/90% water/0.1%TFA; Solvent B: 90% MeOH/10% water/0.1% TFA, wavelength 220 nm.

Examples 115 to 134

The following compounds were synthesized from Example 50 and a varietyof alcohols using the following procedure:3-chloro-7-(4-methylpyridin-3-yl)benzo[d]isoxazole (0.024 g, 0.1 mmol)was dissolved in 12 mL of THF in a 20 mL scintillation vial. To each16×100 mm Wheaton tube containing alcohol was added 0.5 mL of this THFsolution (for total overall concentration of 0.1M) followed by sodiumhydride (4.80 mg, 0.200 mmol). The reaction mixtures were agitated at400 rpm on an INNOVA® platform shaker at room temperature for 10 min.Then to each vial was added 0.50 mL of the core solution and reactionmixtures were agitated at 400 rpm on an INNOVA® platform shaker at roomtemperature for 12 h. Reactions were quenched with MeOH. The reactionmixtures were placed in the SPEEDVAC® to dry for 3 hours at 40° C. Thecrude materials were then re-dissolved in 1.5 mL of DMF and purified onHPLC. The crude material was purified via preparative LC/MS with thefollowing conditions: Column: Waters XBridge C18, 19×250 mm, 5-μmparticles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles;Mobile Phase A: 5:95 MeOH:water with 0.05% TFA; Mobile Phase B: 95:5MeOH:water with 0.05% TFA; Gradient adjusted accordingly to isolateproduct; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation. All compounds wereanalyzed using the following HPLC conditions: Column: Waters XBridgeC18, 4.6×50 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10 mM NH₄OAc; Mobile Phase B: 95:5 acetonitrile:water with 10 mMNH₄OAc; Temperature: 23° C.; Gradient: 0-100% B over 4 minutes, then a1-minute hold at 100% B; Flow: 4 mL/min.

TABLE 2

Ret Ex. R Name [M + H]⁺ time Purity 115

7-(4-methylpyridin-3-yl)-3- phenethoxybenzo[d]isoxazole 331 3.1 100 116

3-(4-chlorophenethoxy)-7-(4- methylpyridin-3-yl)benzo[d] isoxazole 365.22.38 100 117

7-(4-methylpyridin-3-yl)-3- (prop-2-ynyloxy)benzo[d] isoxazole 265.122.41 100 118

3-(3,3-dimethylbutoxy)-7-(4- methylpyridin-3-yl)benzo[d] isoxazole311.27 2.47 100 119

3-(isopentyloxy)-7-(4- methylpyridin-3-yl)benzo[d] isoxazole 297.24 2.35100 120

7-(4-methylpyridin-3-yl)-3- propoxybenzo[d]isoxazole 269.2 2.02 100 121

7-(4-methylpyridin-3-yl)-3-(3- phenylpropoxy)benzo[d] isoxazole 345.252.37 100 122

7-(4-methylpyridin-3-yl)-3-(4- phenylbutoxy)benzo[d]isoxazole 359.262.05 87 123

3-ethoxy-7-(4-methylpyridin-3- yl)benzo[d]isoxazole 255.17 1.82 100 124

7-(4-methylpyridin-3-yl)-3- (naphthalen-2-ylmethoxy)benzo [d]isoxazole367.24 2.41 100 125

3-tert-butoxy-7-(4- methylpyridin-3-yl)benzo[d] isoxazole 283.21 2.15 95126

3-methoxy-7-(4-methylpyridin- 3-yl)benzo[d]isoxazole 241.16 1.61 100 127

3-(benzyloxy)-7-(4- methylpyridin-3-yl)benzo[d] isoxazole 317.19 2.15100 128

3-(4-chlorobenzyloxy)-7-(4- methylpyridin-3-yl)benzo[d] isoxazole 351.172.32 100 129

3-(4-methoxybenzyloxy)-7-(4- methylpyridin-3-yl)benzo[d] isoxazole347.21 2.12 100 130

3-(1-methylpiperidin-4-yloxy)-7- (4-methylpyridin-3-yl)benzo[d]isoxazole 324.23 1.16 100 131

3-isopropoxy-7-(4- methylpyridin-3-yl)benzo[d] isoxazole 269.19 1.99 100132

3-(2-(1H-imidazol-1-yl)ethoxy)- 7-(4-methylpyridin-3-yl)benzo[d]isoxazole 321.05 1.87 100 133

7-(4-methylpyridin-3-yl)-3- (pyrazin-2-ylmethoxy)benzo[d] isoxazole319.18 1.51 92 134

7-(4-methylpyridin-3-yl)-3- (thiazol-2-ylmethoxy)benzo[d] isoxazole324.13 1.7 100

BIOLOGICAL ASSAYS

The pharmacological properties of the compounds of this invention may beconfirmed by a number of biological assays. The exemplified biologicalassays, which follow, have been carried out with compounds of theinvention and/or salts thereof.

CYP17 Total SPA Assay

The assays were performed in U-bottom 384-well optiplates. The finalassay volume was 15 μl prepared from 7.5 μl additions of microsomes(prepared as a high-speed pellet from homogenized HEK2 cells stablytransfected with CYP17), substrates (3H-Pregnenolone and NADPH) and testcompounds in assay buffer (50 mM Potassium phosphate pH 7.2, 10%glycerol). The reaction was initiated by the combination of themicrosomes and substrates in wells containing compound. The reaction wasincubated at room temperature for 45 minutes and terminated by adding7.5 μl of 0.2N HCl to each well. Following an incubation period of 10minutes, anti-DHEA-coated SPA beads were added to the terminatedreaction. The plate was sealed and incubated overnight with shaking at4° C. The beads were allowed to settle in the plate for 1 hour and theplate read on a TOPCOUNT® (Perkin-Elmer) plate reader.

Inhibition data were calculated by comparison to no enzyme controlreactions for 100% inhibition and vehicle-only reactions for 0%inhibition. The final concentration of reagents in the assays are NADPH,2 mM; 3H-Pregnenolone, 1 uM; microsomes, 1.25 ug/ml; Anti-DHEA-SPA beads(0.125 mg/well) in 0.5% Triton X-100 and DMSO, 0.05%. Dose responsecurves were generated to determine the concentration required inhibiting50% of enzyme activity (IC₅₀). Compounds were dissolved at 10 mM indimethylsulfoxide (DMSO) and evaluated at eleven concentrations, each induplicate. IC₅₀ values were derived by non-linear regression analysis.

Table 5 below lists the 1050 values for the following examples of thisinvention measured in the Total CYP17 SPA Assay hereinabove. Thecompounds of the present invention, as exemplified by the followingexamples, showed Human CYP17 SPA IC₅₀ values of less than 1 μM.

TABLE 5 Human CYP17 Inhibition Human CYP17 SPA Example No. 1 IC₅₀ Value(nM) 1 1.1 4 357 6 3.2 14 192 26 65 30 48 52 42 57 524 68 524 86 3.9 9476 98 8.0 99 4.0 103 4.0 109 56 124 611 128 251 129 79CYP17 Lyase Assay

Human CYP17 was expressed in HEK293 cells and microsomal preparationswere made and subsequently used as the source of enzyme in the lyaseassay. The reaction consists of 200 nM [3H]-Hydroxypregnenolone (ARC),200 nM 17-Hydroxypregnenolone (Sigma), 2 mM NADPH (CalBiochem), andCYP17-HEK293 microsomes which were incubated in the presence of DMSO ortest compounds for 20 minutes at room temperature. Compounds weredissolved in DMSO and serially diluted. The reaction was stopped by theaddition of 0.2 N HCl and the product was captured using anti-mouse YSiSPA beads (GE) conjugated to an anti-DHEA monoclonal antibody (Abcam).Signal intensity determined by a Packard Top Count was used to calculatepercent inhibition and IC₅₀ values.

CYP17 Hydroxylase Assay

E. coli was transformed to express active human CYP17 and membranesprepared from the transformed E. coli were used as the source of enzyme.The reaction was carried out in a 50 uL final volume containing 200 nMhCYP17 membranes, 2504 Pregnenolone (Sigma), 7 mM NADPH (CalBiochem), 1μM cytochrome P450 reductase (Invitrogen), and 50 mM sodium phosphatebuffer, pH 7.3. The IC₅₀ determination of compounds dissolved in 100%DMSO was done by serial dilution into the assay buffer to a finalconcentration of 0.2% DMSO. The reaction was incubated at 37° C. for 120minutes and stopped by the addition of 200 uL of 0.02N HCl inacetonitrile. Samples were then spun at 750000 g and 200 uL of thesupernatant was transferred to a clean tube for analysis. The product ofthe reaction, 17 alpha pregnenolone, was measured via LC/MS.

What is claimed is:
 1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: X is O and Y isN; Z is N: Q is:

R¹ is: (i) H, halo, C₁₋₄fluoroalkyl, C₁₋₆alkoxy, C₁₋₄fluoroalkoxy,—S(C₁₋₄fluoroalkyl), —O(C₁₋₄alkylenyl)O(C₁₋₃ alkyl),—O(CH₂)₁₋₄N(C₁₋₃alkyl)₂, —O(C₃₋₆alkynyl), or —O(methylpiperidinyl); (ii)phenyl substituted with zero to 2 substituents independently selectedfrom F, Cl, —CF₃, and/or —OCH₃; (iii) C₃₋₆ cycloalkyl, morpholinyl,thiazolyl, pyridinyl, pyridazinyl, or pyrazinyl; or (iv) —O(CH₂)₁₋₄R^(x)wherein R^(x) is imidazolyl, thiazolyl, phenyl, fluorophenyl,chlorophenyl, methoxyphenyl, naphthalenyl, or pyrazinyl; and R³ is: (i)F, Cl, C₁₋₄alkyl, C₁₋₄alkoxy, or C₁₋₄fluoroalkoxy; (ii) C₃₋₆cyclopropyl,morpholinyl, pyrazolyl, imidazolyl, or triazolyl; (iii) —O(CH₂)₁₋₄R^(y)wherein R^(y) is phenyl, morpholinyl, or pyridazinyl; (iv) pyrrolidinylsubstituted with zero to 2 substituents independently selected from —CH₃and/or —OH; or (v) —NH₂, —NH(C₁₋₄alkyl), —NH(C₂₋₃fluoroalkyl), or—NH(C₃₋₆cycloalkyl).
 2. The compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein: Q is


3. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein: R¹ is: (i) H, Cl, —NH₂, —CH₂CH₂CF₃, C₁₋₆alkoxy,fluoroethoxy, —SCH₂CF₃, —OCH₂CH₂OCH₃, —OCH₂CH₂N(CH₃)₂, —O(CH₂C≡CH), or—O(methylpiperidinyl); (ii) phenyl substituted with zero to 2substituents independently selected from F, Cl, —CF₃, and/or —OCH₃;(iii) cyclopropyl, morpholinyl, thiazolyl, pyridinyl, pyridazinyl, orpyrazinyl; or (iv) —O(CH₂)₁₋₄R^(x) wherein R^(x) is imidazolyl,thiazolyl, phenyl, chlorophenyl, methoxyphenyl, naphthalenyl, orpyrazinyl; and R³ is: (i) Cl, —CH₃, C₁₋₃alkoxy, or fluoroethoxy; (ii)cyclopropyl, morpholinyl, pyrazolyl, imidazolyl, or triazolyl; (iii)—O(CH₂)₁₋₂R^(y) wherein R^(y) is phenyl, morpholinyl, or pyridazinyl;(iv) pyrrolidinyl substituted with —CH₃ and —OH; or (v) —NH₂,—NH(CH₂CF₃), or —NH(cyclopropyl).
 4. The compound according to claim 1or a pharmaceutically acceptable salt thereof, wherein: R¹ is: (i) Cl,—NH₂, —CH₂CH₂CF₃, C₁₋₆alkoxy, fluoroethoxy, —SCH₂CF₃, —OCH₂CH₂OCH₃,—OCH₂CH₂N(CH₃)₂, —O(CH₂C≡CH), or —O(methylpiperidinyl); (ii) phenylsubstituted with zero to 2 substituents independently selected from F,Cl, and/or —OCH₃; (iii) cyclopropyl, thiazolyl, pyridinyl, pyridazinyl,or pyrazinyl; or (iv) —O(CH₂)₁₋₄R^(x) wherein R^(x) is imidazolyl,thiazolyl, phenyl, chlorophenyl, methoxyphenyl, naphthalenyl, orpyrazinyl; and R³ is: (i) Cl, —CH₃, C₁₋₃alkoxy, or fluoroethoxy; (ii)cyclopropyl, morpholinyl, pyrazolyl, imidazolyl, or triazolyl; (iii)—O(CH₂)₁₋₂R^(y) wherein R^(y) is phenyl, morpholinyl, or pyridazinyl;(iv) pyrrolidinyl substituted with —CH₃ and —OH; or (v) —NH₂,—NH(CH₂CF₃), or —NH(cyclopropyl).
 5. The compound according to claim 1or a pharmaceutically acceptable salt thereof, wherein: R¹ is Cl,morpholinyl, or phenyl substituted with zero to 2 substituentsindependently selected from F, Cl, and/or —OCH₃; and R³ is —CH₃ or —NH₂.6. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein: Q is

R¹ is H, pyridinyl, or phenyl substituted with 1 to 2 substituentsindependently selected from F and/or Cl; and R³ is —CH₃ or cyclopropyl.7. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein: R¹ is thiazolyl, pyridinyl, pyrazinyl, or phenylsubstituted with zero to 2 substituents independently selected from F,Cl, and/or —CF₃; and R³ is —CH₃, cyclopropyl, or —NH₂.
 8. The compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof,wherein said compound is:3-(4-Fluorophenyl)-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine(86); 3-Chloro-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine (87);7-(4-Methylpyridin-3-yl)-3-morpholinoisoxazolo[4,5-b]pyridine (88);7-(4-Methylpyridin-3-yl)-3-phenylisoxazolo[4,5-b]pyridine (89);3-(5-Fluoro-2-methoxyphenyl)-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine(90);5-(3-(2-Chloro-4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-amine(91); or5-(3-(4-Fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-amine(92).